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Frontiers in Psychiatry· Xiaoyun Yang·· 2 小时前AI 评分42

抑郁与肌肉骨骼疾病：Frontiers in Psychiatry 发表系统性机制综述框架

Depression and musculoskeletal diseases: a framework of systemic mechanisms

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Frontiers in Psychiatry 发表一篇叙述性综述，提出抑郁通过神经内分泌失调、炎症反应异常、表观遗传修饰、细胞外囊泡通讯紊乱、脑-关节轴神经活动异常及肠道菌群失衡等多条通路影响肌肉骨骼疾病（MSDs）的病理进展。

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Abstract

Musculoskeletal disorders (MSDs) encompass a broad spectrum of conditions affecting bones, joints, and muscles, characterized by significant pain and functional impairment, and have become a major global health burden. In recent years, accumulating evidence has revealed complex bidirectional interactions between depression and musculoskeletal health. This review focuses on depression and delineates how it may influence the pathological progression of MSDs through multiple pathways, including neuroendocrine dysregulation, aberrant inflammatory responses, epigenetic modifications, dysregulated extracellular vesicle-mediated communication, abnormal neural activity along the brain–joint axis, and gut microbiota ecological imbalance. Collectively, depression is associated with an increased risk of MSDs and engages intricate interactions across multiple biological systems. Our study underscores that musculoskeletal disorders are by no means confined to isolated joints or local tissues, but rather represent complex diseases with prominent systemic features. Integrated management strategies combining psychosocial interventions, appropriate physical exercise, and dietary modification hold promise as potential multitargeted approaches for the comprehensive treatment of MSDs.

1 Introduction

MSDs affect approximately 171 million people worldwide, encompassing conditions such as osteoarthritis, rheumatoid arthritis, fibromyalgia, and sarcopenia (1). These disorders are typically associated with chronic pain, physical functional limitations, disability, and other adverse health outcomes, constituting a substantial global health burden. Emerging evidence suggests that MSDs are not purely biomechanical impairments but are profoundly influenced by psychological factors. Depression is a prevalent comorbidity within this population, and its severity has been correlated with exacerbated pain (2). In addition to elevating annual direct medical costs for MSDs patients (3, 4), depression significantly disrupts daily functioning and diminishes quality of life. Critically, it may also dampen pharmacological responsiveness and curtail the benefits of non-pharmacological therapies (5).

Currently, treatment options for MSDs remain relatively limited, with most existing therapies primarily aimed at symptom alleviation—such as the use of non-steroidal anti-inflammatory drugs for pain reduction (6) or physical therapy to improve joint function—yet these approaches are unable to reverse articular cartilage damage or halt disease progression. Interventions targeting negative emotional states have been shown to reduce pain-related distress (7). For instance, tricyclic antidepressants have been found in small-scale trials to alleviate pain in patients with rheumatoid arthritis (8). Duloxetine has been demonstrated to be an effective and safe therapeutic option for patients with fibromyalgia, irrespective of depression (9, 10). Beyond pharmacotherapy, adjunctive psychological interventions, such as cognitive behavioral therapy, whether employed alone or in combination with exercise therapy, have proven effective in reducing depression and distress (11, 12). Collectively, these findings suggest that depression may represent a novel therapeutic target for musculoskeletal pain. Timely identification and management of depressive symptoms in patients with MSDs are therefore essential for the prevention of degenerative musculoskeletal conditions and for the maintenance of both physical and mental well-being.

Despite the growing recognition that depression plays an important role in the pathogenesis of MSDs, the underlying mechanisms remain insufficiently understood. It remains unclear whether this association arises from response biases induced by repetitive negative thinking, immune-mediated mechanisms affecting inflammation, or the combined influence of psychological, behavioral (13), and biological factors (14) on pain perception. Recent investigations have suggested that the pathological basis may stem from multi-system interactions, including dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and hormone secretion (15, 16), immune dysfunction (17, 18), dysregulated lactylation modification, aberrant brain-joint axis (19, 20), and gut microbiota dysbiosis (21–23). This complex, cross-system interaction network establishes a vicious cycle between depression and MSDs. Future interventions should effectively address musculoskeletal conditions by integrating psychological support with muscle-strengthening exercise programs (24).

2 Information sources and search strategy

This is a comprehensive narrative review that employs a structured literature search. The search was designed to ensure broad and transparent coverage of the relevant human and preclinical literature, with eligibility criteria applied pragmatically to prioritize the most informative studies for each mechanistic pathway. We searched MEDLINE (PubMed), Embase (Ovid), and the Web of Science Core Collection from 1 January 1996 to 10 August 2026 (last updated 10 August 2026, Asia/Beijing). The search combined controlled vocabulary (MeSH/Emtree) with free-text keywords for depression and musculoskeletal outcomes; exemplar terms were (“Depressive Disorder” OR “major depressive disorder” OR depression*) AND (“Osteoporosis” OR “Bone Density” OR “Osteoarthritis” OR “Arthritis, Rheumatoid” OR “Sarcopenia” OR fracture* OR BMD), with additional terms emphasizing immunity, inflammation, nerve activity, and microbiota (“Immunity” OR “Inflammatory factor” OR “Hormone” OR “Brain-joint axis” OR “Microbiota” OR microbiom* OR “short-chain fatty acid*” OR SCFA OR butyrate OR “Probiotics” OR “Exercise”) AND bone-related terms. Inclusion criteria encompassed cohort, case–control, and cross-sectional studies linking depression to common musculoskeletal diseases, randomized controlled trials or quasi-experimental studies with musculoskeletal endpoints, relevant systematic reviews, and preclinical studies (animal models and in vitro experiments) that provide mechanistic evidence for the pathways examined in this review. We excluded case reports/series, conference abstracts lacking full data, narrative opinions, and duplicates. Because the review examines both clinical associations and the biological mechanisms that may underlie them, preclinical studies were deliberately retained and are explicitly identified as such in the text. To reduce selection bias, two reviewers independently screened titles/abstracts and full texts, with disagreements resolved by third-party adjudication.

3 Neuroendocrine perturbations and their impact on musculoskeletal homeostasis

3.1 HPA axis

Depression is closely associated with dysregulation of the HPA axis, which serves as the body’s primary stress response system. Chronic or prolonged stress leads to sustained activation of the HPA axis and persistently elevated cortisol secretion, a critical factor contributing to both depression and bone metabolic disorders (25). In healthy subjects, cortisol has been shown to inhibit renal calcium reabsorption, and persistent HPA axis abnormalities can disrupt calcium homeostasis (26), potentially contributing to osteoporosis and rapid bone loss. In vitro, cortisol disrupts bone homeostasis and the synovial fibroblast phenotype in a time-dependent manner: short-term cortisol exposure inhibits osteoblast proliferation, whereas long-term exposure promotes bone resorption by upregulating receptor activator of nuclear factor-κB ligand (RANKL) and downregulating osteoprotegerin (OPG) in osteoblasts (27). These effects also promote bone resorption by enhancing matrix metalloproteinase-13 (MMP-13) activity (28).

3.2 Leptin

Beyond its direct effects on bone, depression-induced cortisol elevation also increases leptin levels via stimulation of leptin resistance (29, 30). Leptin, an adipocyte-derived cytokine-like hormone, exerts complex roles in the regulation of joint pain, neuroimmunity, and bone remodeling. It may function as an immunomodulator, activating intracellular JAK2/STAT3, MAPK/ERK, and PI3K/Akt signaling pathways, thereby participating in peripheral metabolism and central nervous system inflammation (31), which in turn contributes to greater pain severity, symptom burden, and disability in patients with osteoarthritis and fibromyalgia (32). In vitro studies have shown that leptin acts synergistically with inflammatory cytokines such as interferon-γ (33) and interleukin-1β (IL-1β) (34), increasing the production of inducible nitric oxide synthase, prostaglandin E2, and cyclooxygenase-2 in cartilage (35), inducing chondrocyte apoptosis, and directly participating in the process of joint damage.

3.3 Sex hormones

In addition, depression reduces serum levels of testosterone and estrogen (36, 37). Estrogen exerts profound effects on skeletal health by inhibiting osteoclastogenesis and osteoblast apoptosis through the reduction of serum RANKL levels, promoting osteoblast maturation via activation of the Wnt/β-catenin pathway, and increasing OPG levels through upregulation of transforming growth factor-β (38). Consequently, sex hormone imbalance plays a pivotal role in the “neuroendocrine–musculoskeletal” network. In males, it leads to reduced bone mineral density and microstructural deterioration, with a 36% increase in the erosion index and a 16% decrease in bone volume (39, 40). In females, estrogen deficiency disrupts the balance between osteoblastic and osteoclastic activity, reduces bone mineral density, elevates the risk of stress fractures (41), increases the burden of MSDs in postmenopausal women (42), and exacerbates the development of chronic pain (43). Treatment with estrogen (44) or the selective ER modulator raloxifene (45) improved the expression of bone metabolism-related genes and reduced circulating sclerostin levels in postmenopausal women, thereby exerting bone-protective effects. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and their derived exosomes (MSC-Exos) have also been shown to modulate sex hormone homeostasis in male mice, improve the muscle microenvironment, and delay the progression of age-related sarcopenia symptoms (46).

3.4 Prolactin

Furthermore, sex hormone deficiency, in conjunction with HPA axis dysregulation, mediates elevated prolactin levels (47–49). Animal model studies have found that prolactin acts through its receptor (50), upregulates the secretion of inflammatory cytokines—such as tumor necrosis factor-α (TNF-α) and interleukin-1—in osteoblasts, increases the RANKL/OPG ratio, and promotes osteoclast formation and bone resorption (51, 52). Conversely, prolactin also inhibits RANKL secretion from synovial fibroblasts, thereby suppressing the formation of mature osteoclasts (53). Collectively, hormones are directly involved in the onset and progression of depression via central mechanisms, while simultaneously modulating bone homeostasis through both direct effects on bone cells and indirect immunoregulatory pathways.

3.5 Sympathetic nervous system

Osteoblasts and osteoclasts possess receptors for neurotransmitters such as norepinephrine and neuropeptides (54), suggesting that the sympathetic nervous system may exert a direct role in bone homeostasis. Sustained depression leads to marked and prolonged overactivation of the sympathetic nervous system, resulting in increased release of norepinephrine (55) and neuropeptide Y (56). Aberrantly secreted neurotransmitters may mediate the relationship between depression and bone loss by suppressing osteoblast activity (57), leading to reduced bone mineral density in the lumbar spine and femur, accompanied by decreased trabecular microarchitecture in mice (20). The β-adrenergic receptor blocker propranolol has been shown to improve bone mineral density in osteoporotic mice (58). Additionally, neuropeptide Y receptor antagonists have been shown to alleviate cancer-induced bone pain in rats (59). These findings from animal model studies underscore the role of the sympathetic nervous system in bone metabolism and pain.

In summary, depression-related neuroendocrine abnormalities, including HPA axis hyperactivity, fluctuations in leptin and sex hormone levels, elevated prolactin, and alterations in the sympathetic nervous system, can exert systemic effects on the musculoskeletal system through the neuro-immuno-endocrine network. The reduced anti-inflammatory efficacy of cortisol resulting from HPA axis dysregulation, together with abnormal leptin activation, participates in the metabolic and inflammatory process of rheumatoid arthritis, osteoarthritis, and postmenopausal osteoporosis via central regulation and local adipokine effects. However, these mechanisms differ across different MSDs. For instance, the immunostimulatory effect of prolactin is primarily relevant to rheumatoid arthritis, which is characterized by B cell activation and autoantibody production (60), whereas causal evidence is lacking in osteoarthritis, which is centered on cartilage degeneration (61). β2-adrenergic signaling promotes joint destruction in rheumatoid arthritis and is also involved in pain regulation in osteoarthritis (62).

4 Chronic inflammation and immune dysregulation: drivers of tissue degeneration in MSDs

4.1 Immune cells and cytokines

The interconnected nature of depression and musculoskeletal health is rooted in shared immune pathways. Depression can induce systemic activation of the immune system (17, 63). Clinical studies have reported that patients with depression exhibit increased neutrophil and monocyte counts, altered heterogeneity of lymphocytes (T cells and B cells), and reduced natural killer (NK) cell cytotoxicity (64). Neutrophils release OPG and express RANK-L and RANK, participating in bone remodeling in patients with chronic inflammatory arthritis such as rheumatoid arthritis (65). Mouse and in vitro experiments have confirmed that, within the osteoimmune microenvironment, altered T-cell heterogeneity and reduced NK-cell cytotoxic activity lead to insufficient interferon-γ (IFN-γ) secretion (66). IFN-γ exerts osteoprotective effects by inducing TRAF6 degradation to inhibit RANKL-mediated osteoclast differentiation (67). Macrophage polarization (68) and elevated B-cell numbers (69) increase the release of pro-inflammatory cytokines, including interleukin-17, TNF-α, and interleukin-6 (IL-6). The elevation of these pro-inflammatory cytokine levels upregulates RANKL expression on the surface of bone cells, directly stimulating osteoclast differentiation and activity (70), and disrupting bone remodeling homeostasis through pathways such as PI3K/Akt2, AKT/β-catenin (71, 72) and NF-κB (73, 74) (Table 1). Furthermore, inflammatory cytokines such as IL-6 entering the joint cavity can promote matrix degradation, enhance pain sensitivity in patients with osteoarthritis (75), and mediate cartilage degeneration in osteoarthritis. Depression-related immune abnormalities collectively promote osteoclastogenesis, impair the mineralization capacity of osteoblasts, and ultimately lead to bone loss and reduced bone mineral density.

Table 1

PathwayMechanismOutcomesDiseases/species
IL-6SHP2/MEK2/ERK, SHP2/PI3K/Akt2, AKT/β-catenin, Wnt pathway; reduction of the histone H3K27me3 repressive.Inhibit the differentiation of osteoblasts, promote bone resorption; inhibit muscle regeneration; aggravate joint inflammation.Osteoarthritis/human, mice (72); rheumatoid arthritis/human, mice (71); sarcopenia/mice (161).
IL-1β, TNF-αBDNF release; activation NF-κB pathway, RANKL/OPG imbalance, MMP-9 and MMP-13 increase.Inducing osteoblast apoptosis, degradation of bone matrix, central sensitization, muscle atrophyMuscle pain/mice (162); intervertebral disk degeneration/mice (74); rheumatoid arthritis/mice (73); Osteoarthritis/mice (163).
IL-12Drive T cell and NK cell mediated immune response.Aggravate inflammation.Osteoarthritis and rheumatoid arthritis/human (164).
IL-17RANKL/OPG imbalance.Bone loss.Rheumatoid arthritis/mice (70).

Inflammatory factors and musculoskeletal diseases.

4.2 Oxidative stress

Oxidative stress is recognized as a core pathophysiological mechanism underlying depression (76) and exerts profound effects on bone metabolic homeostasis through a multi-step cascade. Studies have shown that reactive oxygen species (ROS) play an important role in RANKL-mediated osteoclastogenesis. RANKL, in turn, promotes ROS production in RAW264.7 pre-osteoclast-like cells in a dose-dependent manner, establishing a vicious cycle (77). Inhibiting the endogenous production of ROS and reducing the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in osteoblasts can exert bone-protective effects (78, 79). Curculigoside stimulates the expression of c-Fos and nuclear factor of activated T cells 1 (NFATc1) through activation of Nrf2, and inhibits the NF-κB pathway to alleviate oxidative stress and osteoclastogenesis, thereby regulating bone metabolism in rat models and osteoblasts (80).

4.3 Immunotherapy

Existing preclinical studies have explored the potential therapeutic efficacy of targeting the immune system in MSDs. For instance, blockade of IL-6 signaling with tocilizumab has been shown to significantly inhibit microglial activation in the spinal dorsal horn of osteoarthritic rats and alleviate mechanical allodynia (81). Anti-TNF-α therapy with etanercept not only ameliorated anhedonia-like behavior in mice but also attenuated joint inflammation (82). Depletion of neutrophils (83) and CD4+ T cells (84) in mouse models has been found to reduce heat hyperalgesia and tactile allodynia. Carnosic acid or irisin can prevent bone loss by promoting Nrf2 nuclear translocation while concurrently inhibiting NF-κB activation (85), and by blocking TRAF6 recruitment to suppress osteoclastogenesis (86). Collectively, the available data not only elucidate the role of depression-mediated immune-related pathophysiology in MSDs but also suggest that this pathway represents a promising therapeutic direction.

Inflammation and MSDs exhibit a shared-skeleton relationship. Inflammatory signaling and immune dysregulation can drive an imbalance between tissue degradation and repair in bone, cartilage, and skeletal muscle. These processes are supported to varying degrees by evidence in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and age-related osteoporosis, constituting the pathological basis of the category of inflammatory musculoskeletal diseases. However, the types of triggers that initiate inflammation, the dominant reactive species involved, and the response patterns of target cells differ across diseases. Rheumatoid arthritis is characterized by excessive free radical production and persistent ROS damage (87). Osteoarthritis, by contrast, is dominated by nitrosative stress (88), with synovial lipid peroxidation levels higher than those in rheumatoid arthritis (89). Therefore, future studies should explicitly specify the triggers, dominant reactive species, and target tissues when reporting inflammatory pathways, so as to distinguish disease-specific inflammatory subtypes.

5 Lactate as a metabolic–epigenetic nexus: reframing musculoskeletal biology

Depression-mediated tissue inflammation creates a hypoxic microenvironment, which shifts cellular metabolism toward anaerobic glycolysis for rapid energy production. Studies have shown that the mRNA levels of lactate dehydrogenase A (LDHA) and glucose transporter 1 in peripheral blood leukocytes of patients with major depressive disorder (90), as well as lactate concentrations in cerebrospinal fluid (91), are significantly elevated, reflecting systemic metabolic alterations. Studies have confirmed that pathological lactate flux can promote disease-specific mechanisms: in rheumatoid arthritis, elevated lactate in the synovium of patients can promote fibroblast proliferation, thereby driving pathological synovial hyperplasia (92); in a mouse model of obesity-related bone disease, it inhibits lipolysis and osteoclastogenesis in bone marrow-derived macrophages by limiting energy regeneration via lysosomal ATP6V0d2 (93); and in rats with osteoarthritis, it exacerbates catabolic and pro-inflammatory responses in chondrocytes (94).

Beyond its role in energy supply, lactate also modulates gene activity through lactylation, a post-translational modification. Upon entering myogenic cells, lactate induces histone lactylation— predominantly at the H3K9 site—which in turn promotes the expression of the Neu2 gene. As a positive regulator of myogenic differentiation, increased Neu2 expression drives myoblast fusion into myotubes, thereby facilitating muscle regeneration in mice (95). Furthermore, lactylation at the H3K18a site within the promoter region of triosephosphate isomerase 1, mediated by LDHA, has been implicated in the progression of osteoarthritis. Knockout of this modification was shown to increase Col2a1 expression and decrease MMP13 expression in arthritic mouse cartilage, thus promoting cartilage repair (96). In addition to histone lactylation, UDP-glucose 6-dehydrogenase (UGDH) has been identified as a key lactylated protein in chondrocytes following lactate treatment, where lactylation at the K6 site directly inhibits its enzymatic activity, thereby exacerbating extracellular matrix degradation and chondrocyte apoptosis in osteoarthritis mice (97). Collectively, these findings indicate that aberrant lactylation in musculoskeletal diseases is associated with disruption of the osteogenic–osteoclastic balance, extracellular matrix homeostasis, and regenerative capacity (94). Neuroendocrine abnormalities, inflammation, and lactate metabolic reprogramming together form a “depression–immune–metabolism” positive feedback loop. Neuroendocrine dysregulation drives inflammation and reshapes metabolism, while lactate and its lactylation modifications, in turn, amplify inflammatory gene expression and metabolic abnormalities through epigenetic regulation, thereby establishing a self-sustaining pathological cycle. The design of molecular agents capable of enhancing or inhibiting specific protein lactylation events, thereby modulating key signaling pathways involved in muscle growth, differentiation, and repair, may represent a novel therapeutic strategy for MSDs. However, substantial preclinical evidence is still required before such approaches can be translated into clinical practice.

6 The role of extracellular vesicles in osteoclast–osteoblast imbalance and muscle atrophy

Since the discovery of extracellular vesicles (EVs), their role in intercellular communication has garnered considerable attention. These vesicles carry a diverse array of bioactive molecules, including proteins and microRNAs (miRNAs), which play critical roles in depression and in the regeneration and pathogenesis of the musculoskeletal system, particularly affecting muscle, cartilage, and joint tissues affected by degeneration. In a rat model of chronic unpredictable mild stress (CUMS), elevated levels of EV-encapsulated miR-126a-3p were detected in serum (92). This miRNA has been shown to inhibit osteogenic differentiation of human adipose-derived mesenchymal stem cells by binding to the 3’-untranslated region (3’-UTR) and suppressing low-density lipoprotein receptor-related protein 6 (LRP6), thereby blocking Wnt signaling activation (98). Similarly, increased serum levels of miR-128-3p in CUMS rats suppress the osteogenic capacity of bone marrow-derived mesenchymal stem cells through targeted inhibition of Smad5 (99). Conversely, certain miRNAs downregulated in serum EVs derived from CUMS rats are also associated with bone remodeling. For instance, miR-455-3p modulates osteoblast proliferation, apoptosis, and oxidative stress via regulation of the HDAC2–Nrf2/ARE signaling pathway, thereby promoting osteoblast growth (100). Unlike endocrine hormones and immune factors, EVs facilitate intercellular communication, modulate immune responses, and promote tissue regeneration through flexible, localized signal delivery, making them promising candidates for future clinical applications in the management of musculoskeletal health and disease. Several ongoing clinical trials offer hope for the treatment of MSDs (101). Nevertheless, the translation of these research findings into clinical practice remains hampered by several challenges, including issues related to large-scale production and isolation, long-term storage and stability, and the development of effective strategies for tissue-specific targeting and delivery.

7 The brain-joint axis: neural circuitry linking depression to peripheral joint pathology

The brain–joint axis relies on interactions between peripheral and central signals. Direct neural projections exist between the joints and the brain, forming a bidirectional communication network through neural, endocrine, and immune pathways (102). Depression induces central neuroinflammation, accompanied by elevated levels of IL-6, TNF-α, and C-reactive protein in the brain (103). Transcriptomic studies have revealed that the upregulation of inflammatory cytokine gene expression in the anterior cingulate cortex sensitizes nociceptive conduction circuits in the spinal dorsal horn and thalamus in rats, thereby participating in pathological pain (104). Animal experiments have shown that excessive inflammatory cytokines lead to aberrant neuronal activity in brain regions such as the medial prefrontal cortex, amygdala, and nucleus accumbens, disrupting glutamate (105) and GABA signaling balance (106), as well as dopaminergic signal transduction (107, 108), thereby amplifying pain and emotional signals. Glutamate acts on neural and joint tissues to induce pain, inflammation, and joint degeneration (105). The glutamate receptor antagonist NBQX significantly reduces joint swelling and degeneration in osteoarthritic mice (109). Basimglurant, a negative allosteric modulator of mGlu5, has also demonstrated potential for mood regulation and pain relief in preclinical trials (110). Dopamine treatment can reverse IL-1β-induced NF-κB activation and JAK2/STAT3 phosphorylation, increase the content of type II collagen and glycosaminoglycans, inhibit cartilage matrix degradation, and ameliorate symptoms in osteoarthritic mice (111). These limbic system structures integrate nociceptive and affective signals, and their aberrant neuronal activity is associated with pain catastrophizing in osteoarthritis patients (112), constituting an independent risk factor for the development of central sensitization in MSDs (113).

Brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), induce electrical currents in the cerebral cortex, which can either excite or inhibit neuronal activity. Activation of cortical neuronal activity by TMS in patients with knee osteoarthritis has been significantly correlated with pain relief (114). Monthly repetitive TMS applied to the contralateral motor cortex has been shown to ameliorate pain and central sensitization in knee osteoarthritis (115). tDCS combined with conventional rehabilitation may exert potential analgesic effects in patients with fibromyalgia and knee osteoarthritis (116). This effect may be mediated by upregulating N-methyl-D-aspartate receptor expression and inhibiting the BDNF/TrkB signaling pathway in the descending pain modulatory system, thereby alleviating pain in osteoarthritic rats (117, 118). Although TMS and tDCS have demonstrated potential for central neuromodulation in MSDs, their clinical translation remains constrained by multiple limitations: therapeutic efficacy shows considerable disease heterogeneity, with the effectiveness of tDCS in chronic low back pain and myofascial pain syndrome remaining unclear (117); and TMS stimulation parameters lack standardized consensus, making direct comparison across studies difficult. Therefore, they may serve as adjunctive therapeutic options rather than universally applicable routine interventions.

8 Gut microbiota as a mediator of depression-induced musculoskeletal pathology: from dysbiosis to systemic inflammation

Depression is closely associated with MSDs and metabolic disturbances, in which gut microbial ecological dysbiosis following stress exposure plays a pivotal role in modulating the progression of musculoskeletal diseases. Clinical studies have demonstrated that Glucagon-Like Peptide-1 (GLP-1), secreted by intestinal L cells, is significantly reduced in patients with depression (119). In GLP-1 receptor knockout mouse models, thyroid calcitonin levels are decreased and osteoclast-induced bone resorption is enhanced, leading to deterioration of normal bone microarchitecture and increased bone fragility. Notably, these effects can be reversed by exogenous GLP-1 receptor agonists (120). In rodents, the GLP-1 receptor agonist liraglutide protects bone by increasing β-catenin and cAMP levels (121–123), while also reducing bone loss and suppressing osteoclastogenesis through downregulation of Trem2, NFATc1, CTSK, and TRAP expression (124). Furthermore, liraglutide targets C2C12 myoblasts to promote muscle formation and function (125). Clinical studies have shown that liraglutide preserves muscle mass in patients with type 2 diabetes to prevent sarcopenia (126) and significantly reduces fracture risk (127).

Depression-related dysbiosis is characterized by a reduction in short-chain fatty acid (SCFA) producing taxa and a decrease in gut microbial alpha diversity. SCFAs such as butyrate play important roles in Treg cell differentiation (128) and in the regulation of inflammation (129, 130). When butyrate levels are diminished, the activation of NF-κB and NLRP3 may become more pronounced, promoting the accumulation of pro-inflammatory mediators such as IL-1β (131, 132). Sustained butyrate release at the colonic site using nanoparticles can modulate gut microbiota composition and downregulate pro-inflammatory responses, thereby alleviating bone loss in mouse models (133). Similarly, multi-strain active probiotics can reshape the gut microenvironment in rats with osteoarthritis and reduce systemic or joint inflammatory markers (134). A Mediterranean diet rich in monounsaturated fatty acids, ω-3 polyunsaturated fatty acids, and dietary fiber has positive effects on reducing pain and improving physical function in patients with rheumatoid arthritis (135); low-energy diets such as low-carbohydrate diets have shown potential in alleviating pain and improving physical function in patients with osteoarthritis (136); and the therapeutic potential of probiotic supplementation in improving bone metabolism and pain in patients with movement disorders has also been recognized (137). Current evidence supports their role in relieving pain, improving musculoskeletal function, and exerting anti-inflammatory effects, offering a practical dietary pattern for patients with musculoskeletal diseases.

Furthermore, appropriate physical exercise (e.g. aerobic, resistance, and combined training) not only ameliorates emotional disturbances and pain in patients with MSDs (138), but also yields sustained improvements in muscle performance and skeletal function (139–150) (Table 2). A single bout of high-intensity exercise has been shown to increase circulating extracellular vesicles enriched in redox-regulating enzymes, which influence vascular structure and function in mouse skeletal muscle in a manner dependent on the antioxidant enzyme glutathione peroxidase 1 (151). Regular moderate-intensity exercise is associated with higher bone mineral density at the lumbar spine and femoral neck, and contributes to a reduced risk of fractures (152). Sustained physical activity also supports gut microbial diversity and SCFA-related metabolism (153), enhances metabolic homeostasis, reshapes body composition (154), suppresses inflammatory responses (155), and preserves muscle function while mitigating muscle atrophy (156). As an effective bridge between psychological intervention and healthy lifestyle management, integrated strategies combining exercise, dietary modulation, and targeted psychological support may yield superior outcomes in pain relief and tissue functional recovery in patients with musculoskeletal conditions. The gut microbiota links environmental factors (such as stress, diet, and exercise) to systemic immune and metabolic status, acting simultaneously on the immune, metabolic, and neuroendocrine systems, thereby providing a practical entry point for lifestyle-based interventions.

Table 2

Musculoskeletal diseasesExercise strategy
Knee osteoarthritisYoga or strengthening exercise (twice weekly for 24 weeks) (141); aerobic exercise (4 and 12weeks) (142); personalised gait retraining (5° or 10°change in foot progression angle) (143).
Rheumatoid arthritisHigh intensity interval training and strength exercise (12weeks) (144, 145); aerobic exercise (twice weekly for 6 weeks) (146).
FibromyalgiaCBT combined with neuromuscular exercise (twice weekly for 8 weeks, with each session lasting 75 to 90 minutes) (147); lifestyle physical activity (five to seven days per week, once for 30minutes) (148).
SarcopeniaProgressive resistance exercise (12 and 24 weeks) (149, 150); high intensity interval training (139)

Neuroimmune pathways and musculoskeletal diseases.

9 Conclusion

The relationship between depression and MSDs has evolved from descriptive associations into a systematic theoretical framework with increasingly well-defined pathogenic mechanisms. This review delineates how depression may contribute to the development of MSDs at multiple levels, encompassing neuroendocrine dysregulation, immune activation, lactylation modification, an aberrant brain-joint axis, and gut microbiota imbalance (Figure 1). Collectively, these interdependent processes constitute a multifactorial network that offers novel perspectives for understanding musculoskeletal disorders as complex inflammatory and degenerative diseases. Furthermore, this framework highlights the regulatory mechanisms spanning from local articular structures to systemic homeostasis, thereby providing a theoretical foundation for the development of therapeutic strategies in MSDs.

Figure 1

The above sections describe distinct biological systems. However, these systems do not operate in parallel or independently, but rather constitute an interconnected network. Existing evidence suggests that this process may follow a temporal sequence: it begins with depression-related chronic stress and neuroendocrine activation, followed by systemic immune and metabolic reprogramming, then tissue-level degeneration, and ultimately central sensitization and pain amplification, after which the brain–joint axis and associated behavioral changes sustain this cycle. This network comprises multiple closely interconnected components, including the HPA–immune axis, the inflammation–lactate–lactylation pathway, the brain–joint pain–limbic neurocircuit, and the gut–immune axis. This also explains why single-target interventions for MSDs have limited efficacy and why multi-system coordinated treatment is required. However, direct longitudinal evidence for this network in humans is currently lacking; therefore, this framework should be regarded as a working model rather than an established sequence.

In the existing literature, most human evidence exploring the association between depression and musculoskeletal disorders comes from cross-sectional surveys (2, 13) or retrospective cohorts (3, 4). Cross-sectional designs cannot distinguish the temporal sequence of “depression leading to musculoskeletal pathology” versus “musculoskeletal pathology leading to depression”, nor can they exclude the possibility of shared third variables. Prospective cohort studies and interventional studies are needed to verify causality. Moreover, much of the evidence synthesized in this review derives from preclinical studies and in vitro experiments. Although these models reproduce some features of human disease, they cannot fully capture the complexity, chronicity, and comorbid burden of clinical depression and MSDs, and species- and time-dependent effects may not directly translate to patients. Definitions and measurement methods for depression vary substantially across studies, ranging from clinician-diagnosed major depressive disorder to self-reported depressive symptoms and stress indices, with these measures differing in severity thresholds and assessment instruments, thereby hindering direct comparison and pooled analysis. Finally, although the molecular targets discussed are promising, they remain at preclinical or early experimental stages, and their safety, efficacy, dosage, and tissue-specific delivery mechanisms in humans have not yet been clarified (94, 101). Therefore, the clinical implications of this framework require validation through prospective, adequately powered studies that prioritize interventional designs.

Beyond the biological framework, these findings carry important implications for psychiatric assessment and public mental health. For MSDs patients, depressive symptoms should be systematically assessed, including somatic manifestations such as pain, fatigue, and sleep disturbances. Early identification and intervention for depression may reduce postoperative complications after musculoskeletal surgery and improve long-term functional outcomes. It should therefore be incorporated into multimodal management frameworks, with screening for depressive symptoms integrated as part of bone health management. Furthermore, given that depressive symptoms often persist beyond the rehabilitation period (157), longitudinal mental health monitoring should be embedded within chronic disease management pathways to identify patients requiring intensified care. Meta-analysis of psychological interventions have confirmed their significant effectiveness in alleviating pain and functional impairment in MSDs patients (158–160). Intervention approaches should be tailored to the severity of depressive symptoms, and practical, feasible practices should be explored in the musculoskeletal field through collaborative care models. Integrating psychological assessment into musculoskeletal health management represents an important step toward the comprehensive, person-centered care model advocated by both psychiatry and musculoskeletal medicine.

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Author contributions

XY: Writing – original draft, Investigation, Validation, Formal analysis. YZ: Investigation, Methodology, Visualization, Writing – original draft. WG: Data curation, Investigation, Writing – original draft. JL: Investigation, Visualization, Writing – original draft. TW: Data curation, Funding acquisition, Investigation, Writing – original draft. JW: Funding acquisition, Writing – review & editing, Formal analysis, Validation. FW: Funding acquisition, Resources, Supervision, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Youth Project of the Shandong Natural Science Foundation (ZR2026QC0868), the General Project of Traditional Chinese Medicine Science and Technology Program of Shandong Province (M20254902), the Yantai Municipal Social Science Planning Research Project (YTSK2026-411) and the Research Project on Monitoring and Statistics of Traditional Chinese Medicine (2025JCTJE77).

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Abbreviations

3’-UTR, 3’-untranslated region; CUMS, Chronic unpredictable mild stress; EVs, Extracellular vesicles; GLP-1, Glucagon-Like Peptide-1; HPA axis, Hypothalamic–pituitary–adrenal axis; IFN-γ, Interferon-gamma; IL-1β, Interleukin-1β; IL-6, Interleukin-6; LDHA, Lactate dehydrogenase A; LRP6, Lipoprotein receptor-related protein 6; miRNAs, microRNAs; MMP-13, Matrix metalloproteinase-13; MSDs, Musculoskeletal disorders; NK cell, Natural killer cell; Nrf2, Nuclear factor erythroid 2-related factor 2; OPG, Osteoprotegerin; RANKL, Receptor Activator of Nuclear factor-κB ligand; SCFA, Short-chain fatty acid; TMS, Transcranial magnetic stimulation; TNF-α, Tumor necrosis factor-α; UGDH, UDP-glucose 6-dehydrogenase.

References

  • 1

    SebbagEFeltenRSagezFSibiliaJDevilliersHArnaudL. The world-wide burden of musculoskeletal diseases: a systematic analysis of the World Health Organization Burden of Diseases Database. Ann Rheum Dis. (2019) 78:844–8. doi: 10.1136/annrheumdis-2019-215142

  • 2

    HeYZhangMLinEHBBruffaertsRPosada-VillaJAngermeyerMCet al. Mental disorders among persons with arthritis: results from the World Mental Health Surveys. Psychol Med. (2008) 38:1639–50. doi: 10.1017/S0033291707002474

  • 3

    JoyceATSmithPKhandkerRMelinJMSinghA. Hidden cost of rheumatoid arthritis (RA): estimating cost of comorbid cardiovascular disease and depression among patients with RA. J Rheumatol. (2009) 36:743–52. doi: 10.3899/jrheum.080670

  • 4

    YangHYSongZSCollinsJELosinaE. Impact of depressive symptoms on direct medical cost among medicare recipients with knee osteoarthritis. Osteoarthritis Cartilage. (2024) 32:922–30. doi: 10.1016/j.joca.2023.12.011

  • 5

    Snoeck HenkemansSVJVisMKocGHLuimeJJKokMRTchetverikovIet al. Association between depression and anxiety and inability to achieve remission in rheumatoid arthritis and psoriatic arthritis. Rheumatol (Oxford). (2025) 64:2411–21. doi: 10.1093/rheumatology/keae621

  • 6

    KolasinskiSLNeogiTHochbergMCOatisCGuyattGBlockJet al. 2019 American college of rheumatology/arthritis foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). (2020) 72:149–62. doi: 10.1002/acr.24131

  • 7

    WadeJBRiddleDLPriceDDDumenciL. Role of pain catastrophizing during pain processing in a cohort of patients with chronic and severe arthritic knee pain. Pain. (2011) 152:314–9. doi: 10.1016/j.pain.2010.10.034

  • 8

    ArnoldLMKeckPEWelgeJA. Antidepressant treatment of fibromyalgia. A meta-analysis and review. Psychosomatics. (2000) 41:104–13. doi: 10.1176/appi.psy.41.2.104

  • 9

    ArnoldLMRosenAPritchettYLD’SouzaDNGoldsteinDJIyengarSet al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. (2005) 119:5–15. doi: 10.1016/j.pain.2005.06.031

  • 10

    ArnoldLMLuYCroffordLJWohlreichMDetkeMJIyengarSet al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. (2004) 50:2974–84. doi: 10.1002/art.20485

  • 11

    LinH-MHsiehP-SChenN-CTsaiC-HKuoW-FLeeY-Let al. Impact of cognitive behavior therapy on osteoarthritis-associated pain, insomnia, depression, fatigue, and physical function in patients with knee/hip osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Front Med (Lausanne). (2022) 9:1083095. doi: 10.3389/fmed.2022.1083095

  • 12

    O’mooreKANewbyJMAndrewsGHunterDJBennellKSmithJet al. Internet Cognitive-Behavioral Therapy for Depression in Older Adults With Knee Osteoarthritis: a randomized controlled trial. Arthritis Care Res (Hoboken). (2018) 70:61–70. doi: 10.1002/acr.23257

  • 13

    MoreiraVMPSSignorelliFSHattoriWTDionisioVC. Association between psychological factors and physical performance in individuals with knee osteoarthritis: a cross-sectional study. J Bodyw Mov Ther. (2025) 42:274–82. doi: 10.1016/j.jbmt.2024.12.030

  • 14

    HertelEArendt-NielsenLOlesenAEAndersenMSPetersenK-S. Quantitative sensory testing, psychological factors, and quality of life as predictors of current and future pain in patients with knee osteoarthritis. Pain. (2024) 165:1719–26. doi: 10.1097/j.pain.0000000000003194

  • 15

    ZhouHZhuHWangJGaoXJiangC. Association between hypothyroidism subtypes and major depression: a two-sample Mendelian randomization study. J Affect Disord. (2024) 351:843–52. doi: 10.1016/j.jad.2024.02.006

  • 16

    HuKAdachiJD. Glucocorticoid induced osteoporosis. Expert Rev Endocrinol Metab. (2019) 14:259–66. doi: 10.1080/17446651.2019.1617131

  • 17

    KöhlerCAFreitasTHMaesMde AndradeNQLiuCSFernandesBSet al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. (2017) 135:373–87. doi: 10.1111/acps.12698

  • 18

    StewartJCRandKLMuldoonMFKamarckTW. A prospective evaluation of the directionality of the depression-inflammation relationship. Brain Behav Immun. (2009) 23:936–44. doi: 10.1016/j.bbi.2009.04.011

  • 19

    LiX-YZhangS-YHongY-ZChenZ-GLongYYuanD-Het al. TGR5-mediated lateral hypothalamus-dCA3-dorsolateral septum circuit regulates depressive-like behavior in male mice. Neuron. (2024) 112:1795–1814.e10. doi: 10.1016/j.neuron.2024.02.019

  • 20

    YirmiyaRGoshenIBajayoAKreiselTFeldmanSTamJet al. Depression induces bone loss through stimulation of the sympathetic nervous system. Proc Natl Acad Sci USA. (2006) 103:16876–81. doi: 10.1073/pnas.0604234103

  • 21

    HodgkinsonKEl AbbarFDobranowskiPManoogianJButcherJFigeysDet al. Butyrate’s role in human health and the current progress towards its clinical application to treat gastrointestinal disease. Clin Nutr. (2023) 42:61–75. doi: 10.1016/j.clnu.2022.10.024

  • 22

    YadavVKRyuJ-HSudaNTanakaKFGingrichJASchützGet al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. (2008) 135:825–37. doi: 10.1016/j.cell.2008.09.059

  • 23

    StillingRMvan de WouwMClarkeGStantonCDinanTGCryanJF. The neuropharmacology of butyrate: the bread and butter of the microbiota-gut-brain axis? Neurochem Int. (2016) 99:110–32. doi: 10.1016/j.neuint.2016.06.011

  • 24

    MusumeciGLoretoCImbesiRTrovatoFMDi GiuntaALombardoCet al. Advantages of exercise in rehabilitation, treatment and prevention of altered morphological features in knee osteoarthritis. a narrative review. Histol Histopathol. (2014) 29:707–19. doi: 10.14670/HH-29.707

  • 25

    LiYNgSKongKJinMFanWZhouWet al. Brain-bone axis dysregulation: biological code underlying the bidirectional association between depression and musculoskeletal disorders. J Orthop Translat. (2026) 56:101044. doi: 10.1016/j.jot.2025.101044

  • 26

    FerrariPBianchettiMGSanssonnensAFreyFJ. Modulation of renal calcium handling by 11 beta-hydroxysteroid dehydrogenase type 2. J Am Soc Nephrol. (2002) 13:2540–6. doi: 10.1097/01.asn.0000028640.78526.0f

  • 27

    BrändströmHBjörkmanTLjunggrenO. Regulation of osteoprotegerin secretion from primary cultures of human bone marrow stromal cells. Biochem Biophys Res Commun. (2001) 280:831–5. doi: 10.1006/bbrc.2000.4223

  • 28

    CanalisEDelanyAM. Mechanisms of glucocorticoid action in bone. Ann N Y Acad Sci. (2002) 966:73–81. doi: 10.1111/j.1749-6632.2002.tb04204.x

  • 29

    BjörntorpP. Do stress reactions cause abdominal obesity and comorbidities? Obes Rev. (2001) 2:73–86. doi: 10.1046/j.1467-789x.2001.00027.x

  • 30

    AdamTCEpelES. Stress, eating and the reward system. Physiol Behav. (2007) 91:449–58. doi: 10.1016/j.physbeh.2007.04.011

  • 31

    AbdelrheemNMAhmedMAEMohamedAFShalabyHNEl SayedNS. Leptin-driven microglial activation in fibromyalgia: mechanistic insights and therapeutic implications. Int Immunopharmacol. (2026) 180:116657. doi: 10.1016/j.intimp.2026.116657

  • 32

    Pérez-MontillaJJGuzmán-GarcíaRPruimboomLNavarro-LedesmaS. Does Leptin and Insulin Levels Influence Pain and Disability in Subjects With Frozen Shoulder? a cross-sectional study. Eur J Pain. (2025) 29:e70007. doi: 10.1002/ejp.70007

  • 33

    OteroMGomez ReinoJJGualilloO. Synergistic induction of nitric oxide synthase type II: in vitro effect of leptin and interferon-gamma in human chondrocytes and ATDC5 chondrogenic cells. Arthritis Rheum. (2003) 48:404–11. doi: 10.1002/art.10811

  • 34

    OteroMLagoRLagoFReinoJJGGualilloO. Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: synergistic effect of leptin with interleukin-1. Arthritis Res Ther. (2005) 7:R581–91. doi: 10.1186/ar1708

  • 35

    VuolteenahoKKoskinenAKukkonenMNieminenRPäivärintaUMoilanenTet al. Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage--mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. Mediators Inflammation. (2009) 2009:345838. doi: 10.1155/2009/345838

  • 36

    ChrousosGPTorpyDJGoldPW. Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications. Ann Intern Med. (1998) 129:229–40. doi: 10.7326/0003-4819-129-3-199808010-00012

  • 37

    Retana-MárquezSBonilla-JaimeHVázquez-PalaciosGMartínez-GarcíaRVelázquez-MoctezumaJ. Changes in masculine sexual behavior, corticosterone and testosterone in response to acute and chronic stress in male rats. Horm Behav. (2003) 44:327–37. doi: 10.1016/j.yhbeh.2003.04.001

  • 38

    KhoslaSMonroeDG. Regulation of bone metabolism by sex steroids. Cold Spring Harb Perspect Med. (2018) 8:a031211. doi: 10.1101/cshperspect.a031211

  • 39

    BenitoMGombergBWehrliFWWeeningRHZemelBWrightACet al. Deterioration of trabecular architecture in hypogonadal men. J Clin Endocrinol Metab. (2003) 88:1497–502. doi: 10.1210/jc.2002-021429

  • 40

    WagnerPPWhittierDEFoesserDBoydSKChapurlatRSzulcP. Bone microarchitecture decline and risk of fall and fracture in men with poor physical performance-the STRAMBO study. J Clin Endocrinol Metab. (2021) 106:e5180–94. doi: 10.1210/clinem/dgab506

  • 41

    RajRDFontalisAGrandhiTSPKimWJGabrAHaddadFS. The impact of the menstrual cycle on orthopaedic sports injuries in female athletes. Bone Joint J. (2023) 105-B:723–8. doi: 10.1302/0301-620X.105B7.BJJ-2022-1262.R2

  • 42

    TanJZhuZWangXYangBLiuSShiMet al. Global burden and trends of musculoskeletal disorders in postmenopausal elderly women: a 1990-2021 analysis with projections to 2045. Arthritis Res Ther. (2025) 27:127. doi: 10.1186/s13075-025-03587-8

  • 43

    PanevinTSBobkovaAOKarateevAEZotkinEG. Endogenous estrogen deficiency and the development of chronic musculoskeletal pain: a review. Ter Arkh. (2022) 94:683–8. doi: 10.26442/00403660.2022.05.201490

  • 44

    FujitaKRoforthMMDemaraySMcGregorUKirmaniSMcCreadyLKet al. Effects of estrogen on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in postmenopausal women. J Clin Endocrinol Metab. (2014) 99:E81–8. doi: 10.1210/jc.2013-3249

  • 45

    ChungYELeeSHLeeS-YKimS-YKimH-HMirzaFSet al. Long-term treatment with raloxifene, but not bisphosphonates, reduces circulating sclerostin levels in postmenopausal women. Osteoporos Int. (2012) 23:1235–43. doi: 10.1007/s00198-011-1675-1

  • 46

    LiNLiuXWangQChenYHanCQuCet al. hUC-MSCs and derived exosomes attenuate DEX-induced muscle atrophy through modulation of estrogen signaling pathway. Stem Cell Res Ther. (2025) 16:419. doi: 10.1186/s13287-025-04328-z

  • 47

    KirkSEXieTYSteynFJGrattanDRBunnSJ. Restraint stress increases prolactin-mediated phosphorylation of signal transducer and activator of transcription 5 in the hypothalamus and adrenal cortex in the male mouse. J Neuroendocrinol. (2017) 29(6):1–9. doi: 10.1111/jne.12477

  • 48

    MeerloPEastonABergmannBMTurekFW. Restraint increases prolactin and REM sleep in C57BL/6J mice but not in BALB/cJ mice. Am J Physiol Regul Integr Comp Physiol. (2001) 281:R846–54. doi: 10.1152/ajpregu.2001.281.3.R846

  • 49

    JaroenpornSNagaokaKKasaharaCOhtaRWatanabeGTayaK. Physiological roles of prolactin in the adrenocortical response to acute restraint stress. Endocr J. (2007) 54:703–11. doi: 10.1507/endocrj.k07-003

  • 50

    Clément-LacroixPOrmandyCLepescheuxLAmmannPDamotteDGoffinVet al. Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice. Endocrinology. (1999) 140:96–105. doi: 10.1210/endo.140.1.6436

  • 51

    SeriwatanachaiDThongchoteKCharoenphandhuNPandaranandakaJTudporKTeerapornpuntakitJet al. Prolactin directly enhances bone turnover by raising osteoblast-expressed receptor activator of nuclear factor kappaB ligand/osteoprotegerin ratio. Bone. (2008) 42:535–46. doi: 10.1016/j.bone.2007.11.008

  • 52

    WongdeeKTulalambaWThongbunchooJKrishnamraNCharoenphandhuN. Prolactin alters the mRNA expression of osteoblast-derived osteoclastogenic factors in osteoblast-like UMR106 cells. Mol Cell Biochem. (2011) 349:195–204. doi: 10.1007/s11010-010-0674-4

  • 53

    Ledesma-ColungaMGAdánNOrtizGSolís-GutiérrezMLópez-BarreraFMartínez de la EscaleraGet al. Prolactin blocks the expression of receptor activator of nuclear factor κB ligand and reduces osteoclastogenesis and bone loss in murine inflammatory arthritis. Arthritis Res Ther. (2017) 19:93. doi: 10.1186/s13075-017-1290-4

  • 54

    TogariA. Adrenergic regulation of bone metabolism: possible involvement of sympathetic innervation of osteoblastic and osteoclastic cells. Microsc Res Tech. (2002) 58:77–84. doi: 10.1002/jemt.10121

  • 55

    WongMLKlingMAMunsonPJListwakSLicinioJProloPet al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci USA. (2000) 97:325–30. doi: 10.1073/pnas.97.1.325

  • 56

    Morales-MedinaJCDumontYQuirionR. A possible role of neuropeptide Y in depression and stress. Brain Res. (2010) 1314:194–205. doi: 10.1016/j.brainres.2009.09.077

  • 57

    FranquinhoFLizMANunesAFNetoELamghariMSousaMM. Neuropeptide Y and osteoblast differentiation--the balance between the neuro-osteogenic network and local control. FEBS J. (2010) 277:3664–74. doi: 10.1111/j.1742-4658.2010.07774.x

  • 58

    TreyballABergeronACBrooksDJLanglaisALHashmiHNaganoKet al. Propranolol promotes bone formation and limits resorption through novel mechanisms during anabolic parathyroid hormone treatment in female C57BL/6J mice. J Bone Miner Res. (2022) 37:954–71. doi: 10.1002/jbmr.4523

  • 59

    Diaz-delCastilloMChristiansenSHAppelCKFalkSWoldbyeDPDHeegaardA-M. Neuropeptide Y is up-regulated and induces antinociception in cancer-induced bone pain. Neuroscience. (2018) 384:111–9. doi: 10.1016/j.neuroscience.2018.05.025

  • 60

    OrbachHShoenfeldY. Hyperprolactinemia and autoimmune diseases. Autoimmun Rev. (2007) 6:537–42. doi: 10.1016/j.autrev.2006.10.005

  • 61

    SilawalSWagnerMRothDBertschTSchwarzSWillauschusMet al. Complement proteins C5/C5a, cathepsin D and prolactin in chondrocytes: A possible crosstalk in the pathogenesis of osteoarthritis. Cells. (2022) 11:1134. doi: 10.3390/cells11071134

  • 62

    Jenei-LanzlZStraubRH. β2-adrenoceptors kick osteoarthritis - Time to rethink prevention and therapy. Osteoarthritis Cartilage. (2024) 32:1522–9. doi: 10.1016/j.joca.2024.06.012

  • 63

    HarsanyiSKupcovaIDanisovicLKleinM. Selected biomarkers of depression: What are the effects of cytokines and inflammation? Int J Mol Sci. (2022) 24:578. doi: 10.3390/ijms24010578

  • 64

    FoleyÉMParkinsonJTMitchellRETurnerLKhandakerGM. Peripheral blood cellular immunophenotype in depression: a systematic review and meta-analysis. Mol Psychiatry. (2023) 28:1004–19. doi: 10.1038/s41380-022-01919-7

  • 65

    PoubellePEChakravartiAFernandesMJDoironKMarceauA-A. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Res Ther. (2007) 9:R25. doi: 10.1186/ar2137

  • 66

    TangMTianLLuoGYuX. Interferon-gamma-mediated osteoimmunology. Front Immunol. (2018) 9:1508. doi: 10.3389/fimmu.2018.01508

  • 67

    TakayanagiHOgasawaraKHidaSChibaTMurataSSatoKet al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. (2000) 408:600–5. doi: 10.1038/35046102

  • 68

    LamJTakeshitaSBarkerJEKanagawaORossFPTeitelbaumSL. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. (2000) 106:1481–8. doi: 10.1172/JCI11176

  • 69

    FischerVHaffner-LuntzerM. Interaction between bone and immune cells: Implications for postmenopausal osteoporosis. Semin Cell Dev Biol. (2022) 123:14–21. doi: 10.1016/j.semcdb.2021.05.014

  • 70

    TyagiAMSrivastavaKMansooriMNTrivediRChattopadhyayNSinghD. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PloS One. (2012) 7:e44552. doi: 10.1371/journal.pone.0044552

  • 71

    TaylorPCFeistEPopeJENashPSibiliaJCaporaliRet al. What have we learnt from the inhibition of IL-6 in RA and what are the clinical opportunities for patient outcomes? Ther Adv Musculoskelet Dis. (2024) 16:1759720X241283340. doi: 10.1177/1759720X241283340

  • 72

    WiegertjesRvan de LooFAJBlaney DavidsonEN. A roadmap to target interleukin-6 in osteoarthritis. Rheumatol (Oxford). (2020) 59:2681–94. doi: 10.1093/rheumatology/keaa248

  • 73

    YuanYMuNLiYGuJChuCYuXet al. TNF-α promotes synovial inflammation and cartilage bone destruction in rheumatoid arthritis via NF-κB/YY1/miR-103a-3p axis. FASEB J. (2025) 39:e70876. doi: 10.1096/fj.202501452R

  • 74

    YangWYuX-HWangCHeW-SZhangS-JYanY-Get al. Interleukin-1β in intervertebral disk degeneration. Clin Chim Acta. (2015) 450:262–72. doi: 10.1016/j.cca.2015.08.029

  • 75

    LeeYCLuBBathonJMHaythornthwaiteJASmithMTPageGGet al. Pain sensitivity and pain reactivity in osteoarthritis. Arthritis Care Res (Hoboken). (2011) 63:320–7. doi: 10.1002/acr.20373

  • 76

    BhattSNagappaANPatilCR. Role of oxidative stress in depression. Drug Discov Today. (2020) 25:1270–6. doi: 10.1016/j.drudis.2020.05.001

  • 77

    AshtarMTenshinHTeramachiJBat-ErdeneAHiasaMOdaAet al. The roles of ROS generation in RANKL-induced osteoclastogenesis: Suppressive effects of febuxostat. Cancers (Basel). (2020) 12:929. doi: 10.3390/cancers12040929

  • 78

    LiXChenYMaoYDaiPSunXZhangXet al. Curcumin protects osteoblasts from oxidative stress-induced dysfunction via GSK3β-Nrf2 signaling pathway. Front Bioeng Biotechnol. (2020) 8:625. doi: 10.3389/fbioe.2020.00625

  • 79

    DomazetovicVMarcucciGFalsettiIBiliaARVincenziniMTBrandiMLet al. Blueberry juice antioxidants protect osteogenic activity against oxidative stress and improve long-term activation of the mineralization process in human osteoblast-like SaOS-2 cells: Involvement of SIRT1. Antioxidants (Basel). (2020) 9:125. doi: 10.3390/antiox9020125

  • 80

    LiuMLiuSZhangQFangYYuYZhuLet al. Curculigoside attenuates oxidative stress and osteoclastogenesis via modulating Nrf2/NF-κB signaling pathway in RAW264.7 cells. J Ethnopharmacol. (2021) 275:114129. doi: 10.1016/j.jep.2021.114129

  • 81

    LinYLiuLJiangHZhouJTangY. Inhibition of interleukin-6 function attenuates the central sensitization and pain behavior induced by osteoarthritis. Eur J Pharmacol. (2017) 811:260–7. doi: 10.1016/j.ejphar.2017.06.032

  • 82

    BrownEMc VeighCJSantosLGogartyMMüllerHKElfvingBet al. TNFα-dependent anhedonia and upregulation of hippocampal serotonin transporter activity in a mouse model of collagen-induced arthritis. Neuropharmacology. (2018) 137:211–20. doi: 10.1016/j.neuropharm.2018.04.023

  • 83

    CarreiraEUCarregaroVTeixeiraMMMoriconiAAraminiAVerriWAet al. Neutrophils recruited by CXCR1/2 signalling mediate post-incisional pain. Eur J Pain. (2013) 17:654–63. doi: 10.1002/j.1532-2149.2012.00240.x

  • 84

    KobayashiYKiguchiNFukazawaYSaikaFMaedaTKishiokaS. Macrophage-T cell interactions mediate neuropathic pain through the glucocorticoid-induced tumor necrosis factor ligand system. J Biol Chem. (2015) 290:12603–13. doi: 10.1074/jbc.M115.636506

  • 85

    ThummuriDNaiduVGMChaudhariP. Carnosic acid attenuates RANKL-induced oxidative stress and osteoclastogenesis via induction of Nrf2 and suppression of NF-κB and MAPK signalling. J Mol Med (Berl). (2017) 95:1065–76. doi: 10.1007/s00109-017-1553-1

  • 86

    KimBLeeKYParkB. Icariin abrogates osteoclast formation through the regulation of the RANKL-mediated TRAF6/NF-κB/ERK signaling pathway in Raw264.7 cells. Phytomedicine. (2018) 51:181–90. doi: 10.1016/j.phymed.2018.06.020

  • 87

    CimenMYCimenOBKaçmazMOztürkHSYorgancioğluRDurakI. Oxidant/antioxidant status of the erythrocytes from patients with rheumatoid arthritis. Clin Rheumatol. (2000) 19:275–7. doi: 10.1007/pl00011172

  • 88

    BentzMZaouterCShiQFahmiHMoldovanFFernandesJCet al. Inhibition of inducible nitric oxide synthase prevents lipid peroxidation in osteoarthritic chondrocytes. J Cell Biochem. (2012) 113:2256–67. doi: 10.1002/jcb.24096

  • 89

    GrigoloBRosetiLFioriniMFacchiniA. Enhanced lipid peroxidation in synoviocytes from patients with osteoarthritis. J Rheumatol. (2003) 30:345–7.

  • 90

    ShibataTYamagataHUchidaSOtsukiKHobaraTHiguchiFet al. The alteration of hypoxia inducible factor-1 (HIF-1) and its target genes in mood disorder patients. Prog Neuro-Psychopharmacol Biol Psychiatry. (2013) 43:222–9. doi: 10.1016/j.pnpbp.2013.01.003

  • 91

    HagiharaHHattoriKKunugiHMiyakawaT. Increased cerebrospinal fluid lactate levels in schizophrenia and major depressive disorder: NCNP Biobank study in Japan. Neuropsychopharmacol Rep. (2026) 46:e70096. doi: 10.1002/npr2.70096

  • 92

    FangKXuJ-XChenX-XGaoX-RHuangL-LDuA-Qet al. Differential serum exosome microRNA profile in a stress-induced depression rat model. J Affect Disord. (2020) 274:144–58. doi: 10.1016/j.jad.2020.05.017

  • 93

    DaiBXuJLiXHuangLHopkinsCWangHet al. Macrophages in epididymal adipose tissue secrete osteopontin to regulate bone homeostasis. Nat Commun. (2022) 13:427. doi: 10.1038/s41467-021-27683-w

  • 94

    XieYUmarMLuoYHuangKLuKLeiYet al. The role of lactylation modifications in musculoskeletal diseases: From mechanism to clinical application. Pharmacol Res. (2025) 221:107976. doi: 10.1016/j.phrs.2025.107976

  • 95

    DaiWWuGLiuKChenQTaoJLiuHet al. Lactate promotes myogenesis via activating H3K9 lactylation-dependent up-regulation of Neu2 expression. J Cachexia Sarcopenia Muscle. (2023) 14:2851–65. doi: 10.1002/jcsm.13363

  • 96

    XiaJQiaoZHaoXZhangY. LDHA-induced histone lactylation mediates the development of osteoarthritis through regulating the transcription activity of TPI1 gene. Autoimmunity. (2024) 57:2384889. doi: 10.1080/08916934.2024.2384889

  • 97

    LanWChenXYuHRuanJKangJNieXet al. UGDH lactylation aggravates osteoarthritis by suppressing glycosaminoglycan synthesis and orchestrating nucleocytoplasmic transport to activate MAPK signaling. Adv Sci (Weinh). (2025) 12:e2413709. doi: 10.1002/advs.202413709

  • 98

    LiHYueLXuHLiNLiJZhangZet al. Curcumin suppresses osteogenesis by inducing miR-126a-3p and subsequently suppressing the WNT/LRP6 pathway. Aging (Albany NY). (2019) 11:6983–98. doi: 10.18632/aging.102232

  • 99

    XuTLuoYWangJZhangNGuCLiLet al. Exosomal miRNA-128-3p from mesenchymal stem cells of aged rats regulates osteogenesis and bone fracture healing by targeting Smad5. J Nanobiotechnology. (2020) 18:47. doi: 10.1186/s12951-020-00601-w

  • 100

    ZhangSWuWJiaoGLiCLiuH. MiR-455-3p activates Nrf2/ARE signaling via HDAC2 and protects osteoblasts from oxidative stress. Int J Biol Macromol. (2018) 107:2094–101. doi: 10.1016/j.ijbiomac.2017.10.080

  • 101

    DaviesOG. Extracellular vesicles: from bone development to regenerative orthopedics. Mol Ther. (2023) 31:1251–74. doi: 10.1016/j.ymthe.2023.02.021

  • 102

    ZhaoYZhangQMengFFanQQiHDuHet al. Regulation of osteoarthritis and associated anxiety-related behaviours by retinoic acid binding protein 2 and its interaction with the insular cortex. Br J Pharmacol. (2026) 183:1048–70. doi: 10.1111/bph.70224

  • 103

    RéusGZManossoLMQuevedoJCarvalhoAF. Major depressive disorder as a neuro-immune disorder: origin, mechanisms, and therapeutic opportunities. Neurosci Biobehav Rev. (2023) 155:105425. doi: 10.1016/j.neubiorev.2023.105425

  • 104

    ZhangYJiangSLiaoFHuangZYangXZouYet al. A transcriptomic analysis of neuropathic pain in the anterior cingulate cortex after nerve injury. Bioengineered. (2022) 13:2058–75. doi: 10.1080/21655979.2021.2021710

  • 105

    WenZ-HChangY-CJeanY-H. Excitatory amino acid glutamate: role in peripheral nociceptive transduction and inflammation in experimental and clinical osteoarthritis. Osteoarthritis Cartilage. (2015) 23:2009–16. doi: 10.1016/j.joca.2015.03.017

  • 106

    ZhaoZ-XSunYLiZ-YWeiJChenTCheJet al. GluK1-containing kainate receptor-dependent long-term depression in the anterior cingulate cortex modulates chronic pain. J Transl Med. (2026) 24:1148. doi: 10.1186/s12967-026-08667-0

  • 107

    MitsiVZachariouV. Modulation of pain, nociception, and analgesia by the brain reward center. Neuroscience. (2016) 338:81–92. doi: 10.1016/j.neuroscience.2016.05.017

  • 108

    JarchoJMMayerEAJiangZKFeierNALondonED. Pain, affective symptoms, and cognitive deficits in patients with cerebral dopamine dysfunction. Pain. (2012) 153:744–54. doi: 10.1016/j.pain.2012.01.002

  • 109

    BonnetCSGilbertSJBlainEJWilliamsASMasonDJ. AMPA/kainate glutamate receptor antagonists prevent posttraumatic osteoarthritis. JCI Insight. (2020) 5:e134055, 134055. doi: 10.1172/jci.insight.134055

  • 110

    FuxeKBorroto-EscuelaDO. Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5. Expert Opin Investig Drugs. (2015) 24:1247–60. doi: 10.1517/13543784.2015.1074175

  • 111

    LuWDingZLiuFShanWChengCXuJet al. Dopamine delays articular cartilage degradation in osteoarthritis by negative regulation of the NF-κB and JAK2/STAT3 signaling pathways. BioMed Pharmacother. (2019) 119:109419. doi: 10.1016/j.biopha.2019.109419

  • 112

    OjedaFMartínez-VilavellaGBlanco-HinojoLDeusJTíoLMonfortJ. Amygdala and nucleus accumbens activation are associated with treatment choice in knee osteoarthritis: an fMRI study. Arthroplasty. (2026) 8:32. doi: 10.1186/s42836-026-00382-x

  • 113

    SariyildizACoskun BenlidayiIOlmez EngizekSDenizV. The relation of psychological status and type D personality with central sensitization in knee osteoarthritis: everything is in your mind! Rheumatol Int. (2023) 43:2261–9. doi: 10.1007/s00296-023-05471-7

  • 114

    SimisMImamuraMde MeloPSMarduyAPacheco-BarriosKTeixeiraPEPet al. Increased motor cortex inhibition as a marker of compensation to chronic pain in knee osteoarthritis. Sci Rep. (2021) 11:24011. doi: 10.1038/s41598-021-03281-0

  • 115

    NguyenJ-PDixneufVEsnautJMorenoASMalineauCNizardJet al. The value of high-frequency repetitive transcranial magnetic stimulation of the motor cortex to treat central pain sensitization associated with knee osteoarthritis. Front Neurosci. (2019) 13:388. doi: 10.3389/fnins.2019.00388

  • 116

    TeixeiraPEPAlawdahLAlhassanHAAGuidettiMPrioriAPapatheodorouSet al. The analgesic effect of transcranial direct current stimulation (tDCS) combined with physical therapy on common musculoskeletal conditions: a systematic review and meta-analysis. Princ Pract Clin Res. (2020) 6:23–6. doi: 10.21801/ppcrj.2020.61.5

  • 117

    LiXZhouWWangLYeYLiT. Transcranial direct current stimulation alleviates the chronic pain of osteoarthritis by modulating NMDA receptors in midbrain periaqueductal gray in rats. J Pain Res. (2022) 15:203–14. doi: 10.2147/JPR.S333454

  • 118

    YeYYanXWangLXuJLiT. Transcranial direct current stimulation attenuates chronic pain in knee osteoarthritis by modulating BDNF/TrkB signaling in the descending pain modulation system. Neurosci Lett. (2023) 810:137320. doi: 10.1016/j.neulet.2023.137320

  • 119

    BianLCaiYZhangYShenLWangHGaoFet al. Microbiota-driven gut-brain signaling underlies antidepressant effects of a GLP-1 analog. Cell Host Microbe. (2026) 34:1000–1017.e5. doi: 10.1016/j.chom.2026.05.003

  • 120

    YamadaCYamadaYTsukiyamaKYamadaKUdagawaNTakahashiNet al. The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology. (2008) 149:574–9. doi: 10.1210/en.2007-1292

  • 121

    LiJFuL-ZLiuLXieFDaiR-C. Glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide alters bone marrow exosome-mediated miRNA signal pathways in ovariectomized rats with type 2 diabetes. Med Sci Monit. (2017) 23:5410–9. doi: 10.12659/msm.906603

  • 122

    WuXLiSXuePLiY. Liraglutide, a glucagon-like peptide-1 receptor agonist, facilitates osteogenic proliferation and differentiation in MC3T3-E1 cells through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), extracellular signal-related kinase (ERK)1/2, and cAMP/protein kinase A (PKA) signaling pathways involving β-catenin. Exp Cell Res. (2017) 360:281–91. doi: 10.1016/j.yexcr.2017.09.018

  • 123

    MengJMaXWangNJiaMBiLWangYet al. Activation of GLP-1 receptor promotes bone marrow stromal cell osteogenic differentiation through β-catenin. Stem Cell Rep. (2016) 6:579–91. doi: 10.1016/j.stemcr.2016.02.002

  • 124

    YuJShiY-CPingFLiWZhangH-BHeS-Let al. Liraglutide inhibits osteoclastogenesis and improves bone loss by downregulating Trem2 in female type 1 diabetic mice: findings from transcriptomics. Front Endocrinol (Lausanne). (2021) 12:763646. doi: 10.3389/fendo.2021.763646

  • 125

    GurjarAAKushwahaSChattopadhyaySDasNPalSChinaSPet al. Long acting GLP-1 analog liraglutide ameliorates skeletal muscle atrophy in rodents. Metabolism. (2020) 103:154044. doi: 10.1016/j.metabol.2019.154044

  • 126

    PernaSGuidoDBolognaCSolerteSBGuerrieroFIsuAet al. Liraglutide and obesity in elderly: efficacy in fat loss and safety in order to prevent sarcopenia. A perspective case series study. Aging Clin Exp Res. (2016) 28:1251–7. doi: 10.1007/s40520-015-0525-y

  • 127

    ChengLHuYLiY-YCaoXBaiNLuT-Tet al. Glucagon-like peptide-1 receptor agonists and risk of bone fracture in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. (2019) 35:e3168. doi: 10.1002/dmrr.3168

  • 128

    LianW-SWangF-SChenY-STsaiM-HChaoH-RJahrHet al. Gut microbiota ecosystem governance of host inflammation, mitochondrial respiration and skeletal homeostasis. Biomedicines. (2022) 10:860. doi: 10.3390/biomedicines10040860

  • 129

    YangYKarampoorSMirzaeiRBorozdkinLZhuP. The interplay between microbial metabolites and macrophages in cardiovascular diseases: a comprehensive review. Int Immunopharmacol. (2023) 121:110546. doi: 10.1016/j.intimp.2023.110546

  • 130

    SarkarAMitraPLahiriADasTSarkarJPaulSet al. Butyrate limits inflammatory macrophage niche in NASH. Cell Death Dis. (2023) 14:332. doi: 10.1038/s41419-023-05853-6

  • 131

    WangWDernstAMartinBLorenziLCadefau-FabregatMPhulphagarKet al. Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation. Cell Rep. (2024) 43:114736. doi: 10.1016/j.celrep.2024.114736

  • 132

    DengMQuFChenLLiuCZhangMRenFet al. SCFAs alleviated steatosis and inflammation in mice with NASH induced by MCD. J Endocrinol. (2020) 245:425–37. doi: 10.1530/JOE-20-0018

  • 133

    YuTBaiRWangZQinYWangJWeiYet al. Colon-targeted engineered postbiotics nanoparticles alleviate osteoporosis through the gut-bone axis. Nat Commun. (2024) 15:10893. doi: 10.1038/s41467-024-55263-1

  • 134

    KorotkyiOHuetADvorshchenkoKKobyliakNFalalyeyevaTOstapchenkoL. Probiotic composition and chondroitin sulfate regulate TLR-2/4-mediated NF-κB inflammatory pathway and cartilage metabolism in experimental osteoarthritis. Probiotics Antimicrob Proteins. (2021) 13:1018–32. doi: 10.1007/s12602-020-09735-7

  • 135

    ForsythCKouvariMD’CunhaNMGeorgousopoulouENPanagiotakosDBMellorDDet al. The effects of the Mediterranean diet on rheumatoid arthritis prevention and treatment: a systematic review of human prospective studies. Rheumatol Int. (2018) 38:737–47. doi: 10.1007/s00296-017-3912-1

  • 136

    AsadiSGrafenauerSBurleyCVFitzgeraldCHumburgPParmenterBJ. The effectiveness of dietary intervention in osteoarthritis management: a systematic review and meta-analysis of randomized clinical trials. Eur J Clin Nutr. (2025) 79:959–71. doi: 10.1038/s41430-025-01622-0

  • 137

    LeiMGuoCWangDZhangCHuaL. The effect of probiotic Lactobacillus casei Shirota on knee osteoarthritis: a randomised double-blind, placebo-controlled clinical trial. Benef Microbes. (2017) 8:697–703. doi: 10.3920/BM2016.0207

  • 138

    GajicPKovacILubinskyGKnezevicNN. Exercise-induced hypoalgesia: cellular and molecular mechanisms linking pain modulation and stress regulation-a narrative review. Cells. (2026) 15:858. doi: 10.3390/cells15100858

  • 139

    SteneGBLequericaMJStensvoldDBalstadTRLydersenSWisløffUet al. Effects of 5 years of aerobic exercise on sarcopenia in older adults-secondary outcomes of the Generation 100 Study. J Cachexia Sarcopenia Muscle. (2026) 17:e70279. doi: 10.1002/jcsm.70279

  • 140

    Etayo-UrtasunPSáez de AsteasuMLIzquierdoM. Physical exercise as an adjuvant to glucocorticoid therapy: clinical recommendations and evidence review. Sports Med. (2026) 56:1287–305. doi: 10.1007/s40279-026-02469-6

  • 141

    AbafitaBJSinghAAitkenDDingCMoonazSPalmerAJet al. Yoga or strengthening exercise for knee osteoarthritis: a randomized clinical trial. JAMA Netw Open. (2025) 8:e253698. doi: 10.1001/jamanetworkopen.2025.3698

  • 142

    YanLLiDXingDFanZDuGJiuJet al. Comparative efficacy and safety of exercise modalities in knee osteoarthritis: systematic review and network meta-analysis. BMJ Clin Res Ed. (2025) 391:e085242. doi: 10.1136/bmj-2025-085242

  • 143

    UhlrichSDMazzoliVSilderAFinlayAKKoganFGoldGEet al. Personalised gait retraining for medial compartment knee osteoarthritis: a randomised controlled trial. Lancet Rheumatol. (2025) 7:e708–18. doi: 10.1016/S2665-9913(25)00151-1

  • 144

    BilbergAMannerkorpiKBorjessonMSvedlundSSivertssonJKlingbergEet al. High-intensity interval training improves cardiovascular and physical health in patients with rheumatoid arthritis: a multicentre randomised controlled trial. Br J Sports Med. (2024) 58:1409–18. doi: 10.1136/bjsports-2024-108369

  • 145

    BilbergABjersingJBörjessonMSivertssonJMannerkorpiK. High-intensity exercise improves multidimensional fatigue and health-related quality of life in rheumatoid arthritis: a randomized controlled study. Arthritis Res Ther. (2025) 27:176. doi: 10.1186/s13075-025-03643-3

  • 146

    BailletAZeboulonNGossecLCombescureCBodinL-AJuvinRet al. Efficacy of cardiorespiratory aerobic exercise in rheumatoid arthritis: meta-analysis of randomized controlled trials. Arthritis Care Res (Hoboken). (2010) 62:984–92. doi: 10.1002/acr.20146

  • 147

    Kashikar-ZuckSWilliamsSEIttenbachRFPeughJThomasSLynch-JordanAMet al. Multicenter randomized controlled trial of cognitive-behavioral, exercise-based, and combined interventions for juvenile fibromyalgia. Pain. (2026) 167:820–31. doi: 10.1097/j.pain.0000000000003840

  • 148

    FontaineKRConnLClauwDJ. Effects of lifestyle physical activity on perceived symptoms and physical function in adults with fibromyalgia: results of a randomized trial. Arthritis Res Ther. (2010) 12:R55. doi: 10.1186/ar2967

  • 149

    HangelbroekRWJKnuimanPTielandMde GrootLCPGM. Attenuated strength gains during prolonged resistance exercise training in older adults with high inflammatory status. Exp Gerontol. (2018) 106:154–8. doi: 10.1016/j.exger.2018.02.008

  • 150

    ShenYShiQNongKLiSYueJHuangJet al. Exercise for sarcopenia in older people: a systematic review and network meta-analysis. J Cachexia Sarcopenia Muscle. (2023) 14:1199–211. doi: 10.1002/jcsm.13225

  • 151

    FlifletAMSpradlinRATanYNishitha VijayanAChoiSJKaoW-Cet al. Exercise training stimulates the release of glutathione peroxidase 1 (GPX1)-enriched extracellular vesicles that promote angiogenesis. FASEB J. (2026) 40:e72052. doi: 10.1096/fj.202505096RR

  • 152

    ZhangY-WWeiPFengL-SDongZ-LHuYZhangHet al. Weekend warrior” physical activity pattern and risk of low bone mass and related fractures: Results from two nationwide population-based surveys. Bone. (2026) 211:117985. doi: 10.1016/j.bone.2026.117985

  • 153

    SaedmocheshiSYousfiNChamariK. Breaking boundaries: the transformative role of exercise in managing multiple sclerosis. EXCLI J. (2024) 23:475–90. doi: 10.17179/excli2024-6932

  • 154

    ShenJPengJLuanYLiuXLiJWuJ. Effects of exercise on metabolic risk, cardiovascular fitness, and body composition in elderly women of the past decade: a systematic review and meta-analysis. J Int Soc Sports Nutr. (2026) 23:2675444. doi: 10.1080/15502783.2026.2675444

  • 155

    XieEHeYCaoTLiCWangZ. Neuroimmune braking mechanisms in exercise-related musculoskeletal injury: from nociceptors to tissue regeneration. J Neuroinflamm. (2026) 23:192. doi: 10.1186/s12974-026-03938-5

  • 156

    BurkeBIValentinoTRIsmaeelAEl-AmouriSSGohJScottLNet al. Exercise-associated microbial metabolites prevent skeletal muscle atrophy in adult female mice. Nat Commun. (2026) 17:4211. doi: 10.1038/s41467-026-74852-w

  • 157

    LarsenJBSkouSTLaursenMBruunNHMadeleinePArendt-NielsenL. Pain mechanisms and psychosocial variables in patients with chronic pain after total knee arthroplasty: secondary analysis from a randomised controlled trial. Eur J Pain. (2025) 29:e70064. doi: 10.1002/ejp.70064

  • 158

    HoE-YChenLSimicMAshton-JamesCEComachioJWangDXMet al. Psychological interventions for chronic, non-specific low back pain: systematic review with network meta-analysis. BMJ Clin Res Ed. (2022) 376:e067718. doi: 10.1136/bmj-2021-067718

  • 159

    ShayganMHosseiniFA. Comparison of the effect of psychosocial skills training on acute and chronic musculoskeletal pain intensity: The effectiveness of early intervention in the reduction of acute musculoskeletal pain. Musculoskeletal Care. (2022) 20:839–47. doi: 10.1002/msc.1635

  • 160

    Moreno-LigeroMMoral-MunozJASalazarAFaildeI. mHealth intervention for improving pain, quality of life, and functional disability in patients with chronic pain: systematic review. JMIR Mhealth Uhealth. (2023) 11:e40844. doi: 10.2196/40844

  • 161

    RipariniGMackenzieMNazFBrooksSJiangKDeewanAet al. Epigenetic dysregulation in aged muscle stem cells drives mesenchymal progenitor expansion via IL-6 and Spp1 signaling. Nat Aging. (2025) 5:2399–416. doi: 10.1038/s43587-025-01002-0

  • 162

    HayashiKLesnakJBPlumbANJanowskiAJSmithAFHillJKet al. Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice. Brain Behav Immun. (2024) 120:471–87. doi: 10.1016/j.bbi.2024.06.019

  • 163

    GongYQiuJYeJJiangTZhangWZhengXet al. AZ-628 delays osteoarthritis progression via inhibiting the TNF-α-induced chondrocyte necroptosis and regulating osteoclast formation. Int Immunopharmacol. (2022) 111:109085. doi: 10.1016/j.intimp.2022.109085

  • 164

    SakkasLIJohansonNAScanzelloCRPlatsoucasCD. Interleukin-12 is expressed by infiltrating macrophages and synovial lining cells in rheumatoid arthritis and osteoarthritis. Cell Immunol. (1998) 188:105–10. doi: 10.1006/cimm.1998.1363

Keywords

brain-joint axis, depression, gut microbiota, lactylation, musculoskeletal disorders, neuroendocrine

Citation

Yang X, Zhao Y, Gao W, Liu J, Wang T, Wang J and Wang F (2026) Depression and musculoskeletal diseases: a framework of systemic mechanisms. Front. Psychiatry 17:1977499. doi: 10.3389/fpsyt.2026.1977499

Received

25 August 2026

Revised

26 September 2026

Accepted

28 September 2026

Published

05 October 2026

Volume

17 - 2026

Edited by

Junquan Liang, Shenzhen Bao’an Traditional Chinese Medicine Hospital, China

Updates

Copyright

© 2026 Yang, Zhao, Gao, Liu, Wang, Wang and Wang.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jingyu Wang, wangjingyu@sdmpu.edu.cn; Feixue Wang, wangfeixue@sdmpu.edu.cn

Disclaimer

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

来源：Frontiers in Psychiatry · frontiersin.org

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