Musculoskeletal Diseases: Mechanisms and Therapeutic Advances

Abstract

Musculoskeletal diseases encompass a broad spectrum of inflammatory, degenerative, and neoplastic disorders that compromise bone and joint function across the lifespan. Increasing evidence highlights the central role of immune regulation in their pathogenesis, driven by complex interactions among immune, bone, and stromal cells. Inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, and dermatomyositis are marked by persistent immune activation and progressive tissue destruction. Degenerative diseases like osteoarthritis, osteoporosis, and intervertebral disc degeneration involve immune senescence, dysregulated tissue remodeling, and inflammation-driven structural damage. Bone and soft tissue tumors-including osteosarcoma, chondrosarcoma, Ewing sarcoma, and soft tissue sarcoma-develop within immunosuppressive niches that hinder antitumor immunity. Notably, these immune environments are not strictly dichotomous but exhibit dynamic, context-dependent states of immune stimulation and suppression. This review delineates both shared and disease-specific immune mechanisms, spanning cytokine networks, signaling pathways, and cellular interactions. It further discusses current and emerging therapeutic strategies, including cytokine modulators, bone-regulatory agents, immune checkpoint inhibitors, and cell-based therapies. Despite recent advances, key challenges persist in translating immunological insights into durable, disease-modifying treatments. By bridging mechanisms across inflammation, degeneration, and malignancy, this review provides an integrated framework for understanding immune contributions to musculoskeletal diseases and identifies promising directions for precision immunotherapy.

Keywords: bone and soft tissue tumors; immune modulation; inflammation; musculoskeletal diseases; precision immunotherapy.

FIGURE 1

Imbalanced immune responses in the rheumatoid arthritis microenvironment. M1 macrophages secrete IL‐6 and TNFα, promoting inflammation and joint destruction. MerTK⁺CD206⁺ resident macrophages reduced; MerTK⁻CD206⁻ infiltrating macrophages expanded during active RA. HBEGF⁺ macrophages enhance fibroblast invasiveness via EGFR signaling. Neutrophils release NETs, expose citrullinated antigens, amplify autoantibody production. Neutrophils produce TNFα, BAFF, and RANKL, contributing to bone erosion. B cells produce TNFα and CCL3 to suppress bone formation; TNFα and RANKL drive osteoclastogenesis. Plasma cells produce RF and ACPAs, forming immune complexes and triggering complement‐mediated joint damage. Th17 cells secrete IL‐17, IL‐21, IL‐22, upregulating RANKL on synovial fibroblasts and activating OCPs. CD11b^−/lowCD115⁺CD117⁺ MDSC–OCP hybrids suppress CD4⁺ and CD8⁺ T cells via nitric oxide; suppression depends on T cell‐derived IFNγ. Tregs produce IL‐10 and TGFβ; express CD25 to consume IL‐2 and suppress effector T cells. Bregs secrete IL‐10, IL‐35, and TGFβ; express PD‐L1 to inhibit T cell activation. Abbreviations: TNFα, tumor necrosis factor alpha; MerTK, Mer tyrosine kinase; HBEGF, heparin‐binding EGF‐like growth factor; EGFR, epidermal growth factor receptor; NETs, neutrophil extracellular traps; BAFF, B cell‐activating factor; RANKL, receptor activator of nuclear factor κB ligand; RF, rheumatoid factor; ACPAs, anticitrullinated protein antibodies; OCPs, osteoclast precursors; MDSC, myeloid‐derived suppressor cell; IFNγ, interferon gamma; TGFβ, transforming growth factor beta; PD‐L1, programmed death‐ligand 1.

FIGURE 2

Immune‐modulatory factors in ankylosing spondylitis. IL‐17–producing Th17 cells, γδT17 cells, and ILC3s drive osteitis and enthesopathy via IL‐17, IL‐22, TNFα, and GM‐CSF. TRBV9⁺CD8⁺ T cells recognize HLA‐B27‐presented peptides, contributing to AS development. Neutrophils release preformed IL‐17 to inflamed sites, amplifying inflammation; activate through CARD9 signaling and promote Th17 polarization. CX3CR1⁺CD59⁺ macrophages activate ILC3s, inducing IL‐17 and IL‐22 production. Macrophage‐derived MIF promotes TNFα secretion from monocytes. Tregs exert immunosuppression via IL‐10 and LAG‐3, inhibiting TNFα, IL‐12, and IL‐23 production by monocytes. MDSCs suppress T cell responses via pSTAT3–arginase‐I signaling. Abbreviations: ILC3s, group 3 innate lymphoid cells; TNFα, tumor necrosis factor alpha; GM‐CSF, granulocyte–macrophage colony‐stimulating factor; TRBV9, T cell receptor beta variable 9; HLA‐B27, human leukocyte antigen B27; CARD9, caspase recruitment domain‐containing protein 9; MIF, macrophage migration inhibitory factor; LAG‐3, lymphocyte activation gene‐3; MDSCs, myeloid‐derived suppressor cells; pSTAT3, phosphorylated signal transducer and activator of transcription 3; arginase‐I, arginase type I.

FIGURE 3

Immune‐modulatory factors in osteoarthritis. M1 macrophages attack tissue cells and are activated by ECM degradation products acting as DAMPs. These bind to TLRs and trigger NF‐κB and NLRP3 inflammasome signaling, reinforcing M1 polarization. Macrophages upregulate MMPs (e.g., MMP‐1, ‐3, ‐9, ‐13) and inflammatory cytokines (IL‐1β, TNFα, IL‐6, IL‐8, IFNγ) in chondrocytes; chondrocytes, in turn, stimulate macrophages to produce IL‐1β and VEGF‐A. M1 macrophages contribute to osteophyte formation and subchondral bone remodeling via TGFβ, BMP‐2, and Rspo2. FLS produce inflammatory cytokines (e.g., IL‐6, IL‐8, TNFα) and MMPs (e.g., MMP‐1, ‐3, ‐13), promoting cartilage degradation and synovial fibrosis. THY1⁺HLA‐DR^high FLS in the sublining layer exhibit proinflammatory phenotypes (e.g., IL‐6, CCL2, CXCL12), while DKK3⁺ FLS may counter cartilage breakdown. α‐SMA⁺ myofibroblast‐like FLS in both lining and sublining layers promote ED‐A‐F overproduction, driving TNFα expression in macrophages. CD55⁺THY1⁻ lining FLS mediate aberrant bone formation through BMP‐6 signaling. T cells secrete IL‐17 and TNFα, enhancing MMP production (e.g., MMP‐9) by synovial fibroblasts and resident cells, thereby accelerating ECM degradation and damage to periarticular structures. Tregs and Bregs suppress inflammation through IL‐10 secretion. Abbreviations: ECM, extracellular matrix; DAMPs, damage‐associated molecular patterns; TLRs, Toll‐like receptors; NF‐κB, nuclear factor kappa B; NLRP3, NOD‐, LRR‐ and pyrin domain‐containing protein 3; MMPs, matrix metalloproteinases; TNFα, tumor necrosis factor alpha; IFNγ, interferon gamma; VEGF‐A, vascular endothelial growth factor A; TGFβ, transforming growth factor beta; BMP‐2, bone morphogenetic protein 2; Rspo2, R‐spondin 2; FLS, fibroblast‐like synoviocytes; THY1, thymocyte antigen 1; HLA‐DR, human leukocyte antigen–DR isotype; DKK3, dickkopf WNT signaling pathway inhibitor 3; α‐SMA, alpha‐smooth muscle actin; ED‐A‐F, extra domain A fibronectin; BMP‐6, bone morphogenetic protein 6.

FIGURE 4

Skewed immune scenario in osteoporosis. Macrophages differentiate into osteoclasts under stimulation by M‐CSF and RANKL. TNFα secreted by macrophages amplifies RANK/RANKL signaling to promote osteoclastogenesis while concurrently suppressing osteoblast differentiation via downregulation of IGF‐1 and RUNX2. Aging leads to the accumulation of senescent macrophages that release SASP factors, driving M1 polarization and paracrine senescence, forming a self‐perpetuating loop contributing to senile osteoporosis. M2 macrophages promote osteoblast differentiation via secretion of BMP‐2, TGFβ, and IGF‐1, and exert anti‐inflammatory effects through IL‐10. Activated T cells, especially Th17 cells, secrete RANKL, TNFα, IL‐6, and IL‐17, directly enhancing osteoclast differentiation and activity. CTLA‐4 expressed on Tregs binds to OCPs and inhibits their differentiation in a dose‐dependent manner. Treg‐derived IL‐10 mediates suppression of T cell proliferation and contributes to bone‐protective immune regulation. Treg migration and the production of IL‐10 and TGFβ are dependent on RANKL signaling. Bregs suppress osteoporosis via IL‐10 secretion and modulate osteoblast activity through TGFβ. Abbreviations: M‐CSF, macrophage colony‐stimulating factor; RANKL, receptor activator of nuclear factor κB ligand; TNFα, tumor necrosis factor alpha; IGF‐1, insulin‐like growth factor 1; RUNX2, runt‐related transcription factor 2; SASP, senescence‐associated secretory phenotype; BMP‐2, bone morphogenetic protein 2; TGFβ, transforming growth factor beta; CTLA‐4, cytotoxic T‐lymphocyte‐associated protein 4; OCPs, osteoclast precursors.

FIGURE 5

Mechanistic overview of immune cell contributions to tendinopathy. Extracellular mitochondrial particles released from mechanically overloaded tendon cells recruit and activate inflammatory macrophages, driving IL‐6, CXCL1, and IL‐18 production and enhancing chemotaxis. Infiltrating M1 macrophages amplify inflammatory signaling, impair TSPC differentiation, and release IL‐1β via NF‐κB/NLRP3 pathways, exacerbating degeneration; together with mast cells and T cells, they also promote IL‐17A production, further amplifying inflammation, stimulating type III collagen synthesis, and disrupting matrix remodeling. Mast cells, recruited by substance P, contribute to inflammation and pain through IL‐17A secretion and nerve interactions, while degranulation releases histamine, prostaglandins, and tryptase, inducing hyperalgesia, fibrosis, and neovascularization. Mast cell‐derived mediators further upregulate COX‐2/PGE2 and MMPs in tenocytes, suppressing type I collagen synthesis and accelerating ECM degradation. Neutrophils infiltrate peritendinous tissue early after injury, initiating the inflammatory cascade. In contrast, CD146⁺ TSPCs promote M2 macrophage polarization and repair, but diseased tendons show reduced M2 populations, sustaining a proinflammatory milieu. Abbreviations: NF‐κB, nuclear factor kappa B; NLRP3, NOD‐, LRR‐, and pyrin domain‐containing protein 3; TSPCs, tendon stem/progenitor cells; COX‐2, cyclooxygenase‐2; PGE2, prostaglandin E2; MMPs, matrix metalloproteinases; ECM, extracellular matrix.

FIGURE 6

Mechanisms of immune evasion in the osteosarcoma microenvironment. T cell recruitment impaired by epigenetic silencing of CXCL12 in osteosarcoma cells. Osteosarcoma cells upregulate CXCL8, inducing PD‐L1 expression on CD8⁺ T cells and suppressing cytotoxicity. NK cells recognize tumor cells via HLA class I downregulation and CD54/CD58 upregulation. FSTL1 overexpression in osteosarcoma induces NK cell apoptosis and activates the ALCAM–CD6 immunosuppressive axis. DC dysfunction linked to immune evasion. TAMs promote tumor progression via exosomal miR‐221‐3p (↓SOCS3, ↑JAK2/STAT3), NECTIN2–TIGIT and CD86–CTLA4 suppression of T cells, secretion of COX‐2/IL‐1β for lymphangiogenesis, and stimulation of PURPL release (↓miR‐363, ↑PDZD2). HMGB1 and PURPL from tumor cells drive TAM polarization. CXCL12/CXCR4 chemotaxis recruits MDSCs and promotes survival via PI3K/AKT signaling; cAMP/PKA pathway further activates MDSCs. Activated MDSCs inhibit T cells and secrete IL‐23 to promote tumor growth. Tregs suppress IFNγ and IL‐12 production via IL‐35 and Gal9–Tim3 interaction. Osteosarcoma promotes CAF differentiation via exosomal COL6A1 and TGFβ, and through linc00881 (↓miR‐29c‐3p, ↑NF‐κB). Activated CAFs secrete TGF to upregulate COL6A1, promoting EMT and metastasis. CAF‐derived SNHG17 (↓miR‐2861) upregulates MMP2; miR‐1228 downregulates SCAI to enhance invasion. Abbreviations: PD‐L1, programmed death‐ligand 1; HLA, human leukocyte antigen; FSTL1, follistatin‐like 1; ALCAM, activated leukocyte cell adhesion molecule; TAMs, tumor‐associated macrophages; SOCS3, suppressor of cytokine signaling 3; JAK2, Janus kinase 2; STAT3, signal transducer and activator of transcription 3; NECTIN2, nectin cell adhesion molecule 2; TIGIT, T cell immunoreceptor with Ig and ITIM domains; CTLA4, cytotoxic T‐lymphocyte‐associated protein 4; COX‐2, cyclooxygenase‐2; PURPL, p53 upregulated regulator of p53 levels; PDZD2, PDZ domain containing 2; HMGB1, high‐mobility group box 1; MDSCs, myeloid‐derived suppressor cells; PI3K, phosphoinositide 3‐kinase; AKT, protein kinase B; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; IFNγ, interferon gamma; Gal9, galectin‐9; Tim3, T cell immunoglobulin and mucin domain‐containing protein 3; CAF, cancer‐associated fibroblast; COL6A1, collagen type VI alpha 1 chain; TGFβ, transforming growth factor beta; NF‐κB, nuclear factor kappa B; SNHG17, small nucleolar RNA host gene 17; MMP2, matrix metalloproteinase 2; SCAI, suppressor of cancer cell invasion.