Macrophage-driven pathological ossification of the posterior longitudinal ligament: mechanistic insights and therapeutic opportunities

Abstract

Ossification of the posterior longitudinal ligament (OPLL) is a chronic degenerative spinal condition in which bone gradually forms within the ligament, compressing the spinal cord and causing progressive neurological decline. While genetic predisposition and metabolic disturbances are well-recognized contributors, growing evidence points to macrophages as central players in shaping the tissue environment that drives pathological bone formation. Macrophages are remarkably plastic cells whose phenotypes and functions are continuously molded by cues from their local tissue environment. While pro-inflammatory macrophages sustain chronic low-grade inflammation through cytokine release and matrix remodeling, anti-inflammatory macrophages paradoxically amplify disease progression by driving fibrotic remodeling, excessive matrix accumulation, and aberrant vascularization, collectively fostering a hypoxic, ossification-prone niche within the ligament. Supporting this notion, similar macrophage-mediated mechanisms have been described in heterotopic ossification, though OPLL represents a distinct pathological process. This review synthesizes current evidence on how macrophages shape the OPLL microenvironment, draws mechanistic connections between macrophage activity and disease progression, and explores whether targeting these cells could open new therapeutic avenues.

References

[1] Hasegawa T. The essence of clinical practice guidelines for ossification of spinal ligaments, 2019: 1. Epidemiology of OPLL. Spine Surg. Relat. Res., 2021, 5: 318-321

[2] Endo T, et al.. Strong relationship between dyslipidemia and the ectopic ossification of the spinal ligaments. Sci. Rep., 2022, 12 22617

[3] Nakajima M, et al.. A genome-wide association study identifies susceptibility loci for ossification of the posterior longitudinal ligament of the spine. Nat. Genet., 2014, 46: 1012-1016

[4] Nakajima M, Kou I, Ohashi H. Identification and functional characterization of RSPO2 as a susceptibility gene for ossification of the posterior longitudinal ligament of the spine. Am. J. Hum. Genet., 2016, 99: 202-207

[5] Koike Y, et al.. Genetic insights into ossification of the posterior longitudinal ligament of the spine. eLife, 2023, 12 e86514

[6] Miura S, et al.. Visceral fat obesity predicts ossification of the posterior longitudinal ligament: annual health examination data-based evidence. Spine J., 2025, 25: 1428-1439

[7] Sato T, et al.. Visceral fat and ossification of the posterior longitudinal ligament: insights from a Japanese cohort. JB JS Open Access, 2025, 10: e25.00195

[8] Williams R, Periasamy M. Genetic and environmental factors contributing to visceral adiposity in Asian populations. Endocrinol. Metab., 2020, 35: 681-695

[9] Kadowaki T, et al.. Japanese men have larger areas of visceral adipose tissue than Caucasian men at the same levels of waist circumference in a population-based study. Int. J. Obes., 2006, 30: 1163-1165

[10] Nazare JA, et al.. Ethnic influences on the relations between abdominal subcutaneous and visceral adiposity, liver fat, and cardiometabolic risk profile. Am. J. Clin. Nutr., 2012, 96: 714-726

[11] Ogawa W, et al.. Definition, criteria, and core concepts of guidelines for the management of obesity disease in Japan. Endocr. J., 2024, 71: 223-231

[12] Fukada S, et al.. Dyslipidemia as a novel risk for the development of symptomatic ossification of the posterior longitudinal ligament. Spine J., 2023, 23: 1287-1295

[13] Endo T, Takahata M, Koike Y, Iwasaki N. Clinical characteristics of patients with thoracic myelopathy caused by ossification of the posterior longitudinal ligament. J. Bone Miner. Metab., 2020, 38: 63-69

[14] Singh M, Kuharski M, Balmaceno-Criss M, Diebo BG, Daniels A. Hyperlipidemia, obesity, and diabetes, and risk of ossification of the posterior longitudinal ligament. World Neurosurg., 2024, 188: e642-e647

[15] Weimershaus M, et al.. Mast cell-mediated inflammation relies on insulin-regulated aminopeptidase controlling cytokine export from the Golgi. J. Allergy Clin. Immunol., 2023, 151: 1595-1608.e6

[16] Zlatanova M, Grubač J, Trbojević-Ivić J, Gavrović-Jankulović M. Phenotypic changes and oxidative stress in THP-1 macrophages in response to vanilloids following stimulation with allergen Act d 1 and LPS. Antioxidants, 2025, 14: 949

[17] Li W, et al.. Recombinant Treponema pallidum protein Tp0768 promotes proinflammatory cytokine secretion of macrophages through ER stress and ROS/NF-κB pathway. Appl. Microbiol. Biotechnol., 2021, 105: 353-366

[18] Jain SK, Rains JL, Croad JL. High glucose and ketosis (acetoacetate) increases, and chromium niacinate decreases, IL-6, IL-8, and MCP-1 secretion and oxidative stress in U937 monocytes. Antioxid. Redox Signal., 2007, 9: 1581-1590

[19] Mia MM, et al.. YAP/TAZ are crucial regulators of macrophage-mediated pulmonary inflammation and fibrosis after bleomycin-induced injury. Eur. Respir. J., 2025, 65: 2301544

[20] Aschner Y, Downey GP. Transforming growth factor-β: master regulator of the respiratory system in health and disease. Am. J. Respir. Cell Mol. Biol., 2016, 54: 647-655

[21] Tanno M, Furukawa KI, Ueyama K, Harata S, Motomura S. Uniaxial cyclic stretch induces osteogenic differentiation and synthesis of bone morphogenetic proteins of spinal ligament cells derived from patients with ossification of the posterior longitudinal ligaments. Bone, 2003, 33: 475-484

[22] Xu L, et al.. Galectin-3 enhances osteogenic differentiation of precursor cells from patients with diffuse idiopathic skeletal hyperostosis via Wnt/β-catenin signaling. J. Bone Miner. Res., 2022, 37: 724-739

[23] Liu Q, et al.. Nano-sized hydroxyapatite induces apoptosis and osteogenic differentiation of vascular smooth muscle cells via JNK/c-JUN pathway. Int. J. Nanomed., 2021, 16: 3633-3648

[24] Wang L, et al.. Sorafenib inhibits ossification of the posterior longitudinal ligament by blocking LOXL2-mediated vascularization. Bone Res., 2024, 12: 24

[25] Mass E, Lachmann N. From macrophage biology to macrophage-based cellular immunotherapies. Gene Ther., 2021, 28: 473-476

[26] Terkawi MA, Kadoya K, Endo T. Editorial: Macrophages: allies or merciless enemies in musculoskeletal systems. Front. Immunol., 2025, 16 1746089

[27] Gomez Perdiguero E, et al.. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature, 2015, 518: 547-551

[28] Roquilly A, Mintern JD, Villadangos JA. Spatiotemporal adaptations of macrophage and dendritic cell development and function. Annu. Rev. Immunol., 2022, 40: 525-557

[29] Park MD, Silvin A, Ginhoux F, Merad M. Macrophages in health and disease. Cell, 2022, 185: 4259-4279

[30] Xue J, et al.. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity, 2014, 40: 274-288

[31] Tannahill GM, et al.. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature, 2013, 496: 238-242

[32] Xiong A, Liu Y. Targeting hypoxia-inducible factors-1α as a novel therapy in fibrosis. Front. Pharmacol., 2017, 8: 326

[33] Liu X, et al.. Angiogenesis in ossification of the posterior longitudinal ligament: progress from mechanism to targeted intervention. Front. Cell Dev. Biol., 2026, 14 1707176

[34] Semenza GL. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer, 2003, 3: 721-732

[35] Robins JC, et al.. Hypoxia induces chondrocyte-specific gene expression in mesenchymal cells in association with transcriptional activation of Sox9. Bone, 2005, 37: 313-322

[36] Wang H, Kaplan FS, Pignolo RJ. The HIF-1α and mTOR pathways amplify heterotopic ossification. Biomolecules, 2024, 14: 147

[37] Li M, et al.. Signaling pathways in macrophages: molecular mechanisms and therapeutic targets. MedComm, 2023, 4 e349

[38] Strizova Z, et al.. M1/M2 macrophages and their overlaps—myth or reality?. Clin. Sci., 2023, 137: 1067-1093

[39] Weivoda MM, Bradley EW. Macrophages and bone remodeling. J. Bone Miner. Res., 2023, 38: 359-369

[40] Liu G, et al.. M2 macrophage-derived exosomes for osteonecrosis of femoral head treatment: modulating neutrophil extracellular traps formation and endothelial phenotype transition. Bone Res., 2025, 13: 42

[41] Wculek SK, et al.. Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis. Immunity, 2023, 56: 516-530.e9

[42] Cui Y, et al.. The role of AMPK in macrophage metabolism, function and polarisation. J. Transl. Med., 2023, 21 892

[43] Purohit M, et al.. Janus kinase/signal transducers and activator of transcription (JAK/STAT) and its role in lung inflammatory disease. Chem. Biol. Interact., 2023, 371 110334

[44] Lee TE, Shin KC, Park JB, Oh DK. Specialized pro-resolving mediators: biosynthetic pathways, biocatalytic synthesis, and applications. Biotechnol. Adv., 2025, 84 108682

[45] Meguro K, et al.. SOCS3 expressed in M2 macrophages attenuates contact hypersensitivity by suppressing MMP-12 production. J. Investig. Dermatol., 2016, 136: 649-657

[46] Chen L, Kadoya K, Endo T, Iwasaki N, Terkawi MA. Efferocytosis at the frontline of homeostasis: shaping the bone microenvironment and therapeutic implications in related diseases. Cytokine Growth Factor Rev., 2025, 83: 85-98

[47] Li S, et al.. Cell communication and relevant signaling pathways in osteogenesis-angiogenesis coupling. Bone Res., 2025, 13: 45

[48] Wu F, et al.. Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation. Bone Res., 2025, 13: 7

[49] Shi L, et al.. Identification of novel macrophages and bone morphogenetic protein signals causing ectopic calcification and impairing muscle regeneration. iScience, 2025, 28 112841

[50] Wang YY, et al.. Macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. J. Am. Soc. Nephrol., 2017, 28: 2053-2067

[51] Zhao Y, et al.. Cellular senescence promotes macrophage-to-myofibroblast transition in chronic ischemic renal disease. Cell Death Dis., 2025, 16 372

[52] Tang PC, et al.. Hematopoietic transcription factor RUNX1 is essential for promoting macrophage-myofibroblast transition in non-small-cell lung carcinoma. Adv. Sci., 2024, 11 e2302203

[53] Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat. Rev. Nephrol., 2016, 12: 325-338

[54] Katoh K. Integrin and its associated proteins as a mediator for mechano-signal transduction. Biomolecules, 2025, 15: 166

[55] Tang Y, et al.. Mechanosensitive Piezo1 protein as a novel regulator in macrophages and macrophage-mediated inflammatory diseases. Front. Immunol., 2023, 14 1149336

[56] Mei F, et al.. Matrix stiffness regulates macrophage polarisation via the Piezo1-YAP signalling axis. Cell Prolif., 2024, 57 e13640

[57] Tu PC, et al.. Mechanical stretch promotes macrophage polarization and inflammation via the RhoA-ROCK/NF-κB pathway. Biomed. Res. Int., 2022, 2022 6871269

[58] Zeng W, et al.. Functional polarization of tumor-associated macrophages dictated by metabolic reprogramming. J. Exp. Clin. Cancer Res., 2023, 42: 245

[59] Liu, Y. et al. Metabolic reprogramming in macrophage responses. Biomark. Res.9, 1 (2021).

[60] van Dierendonck XAMH, et al.. Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages. Proc. Natl. Acad. Sci. USA, 2022, 119 e2114739119

[61] Bosch M, et al.. Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense. Science, 2020, 370 eaay8085

[62] Zingg JM, Vlad A, Ricciarelli R. Oxidized LDLs as signaling molecules. Antioxidants, 2021, 10: 1184

[63] Tall AR, Bornfeldt KE. Inflammasomes and atherosclerosis: a mixed picture. Circ. Res., 2023, 132: 1505-1520

[64] Anand PK. From fat to fire: the lipid-inflammasome connection. Immunol. Rev., 2025, 329 e13403

[65] Huang Y, et al.. Macrophages in heterotopic ossification: from mechanisms to therapy. npj Regen. Med., 2021, 6: 70

[66] Takahata M, et al.. Adipokine dysregulation as an underlying pathology for diffuse ectopic ossification of spinal posterior longitudinal ligament in patients with obesity. Spine J., 2025, 25: 80-90

[67] Saito H, et al.. Increased cellular expression of interleukin-6 in patients with ossification of the posterior longitudinal ligament. Spine, 2023, 48: E78-E86

[68] Guo D, et al.. Rspo2 exacerbates rheumatoid arthritis by targeting aggressive phenotype of fibroblast-like synoviocytes and disrupting chondrocyte homeostasis via Wnt/β-catenin pathway. Arthritis Res. Ther., 2023, 25: 217

[69] Pajarinen J, et al.. Mesenchymal stem cell–macrophage crosstalk and bone healing. Biomaterials, 2019, 196: 80-89

[70] Abaricia JO, Shah AH, Chaubal M, Hotchkiss KM, Olivares-Navarrete R. Wnt signaling modulates macrophage polarization and is regulated by biomaterial surface properties. Biomaterials, 2020, 243 119920

[71] Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature, 2013, 496: 445-455

[72] Fu YL, Harrison RE. Microbial phagocytic receptors and their potential involvement in cytokine induction in macrophages. Front. Immunol., 2021, 12 662063

[73] Morimoto K, Janssen WJ, Terada M. Defective efferocytosis by alveolar macrophages in IPF patients. Respir. Med., 2012, 106: 1800-1803

[74] Shi H, et al.. Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction-associated steatohepatitis. Sci. Transl. Med., 2025, 17 eadv2106

[75] Wang J, et al.. Gut microbial nordihydroguaiaretic acid suppresses macrophage pyroptosis to regulate epithelial homeostasis and inflammation. Gut Microbes, 2025, 17 2518338

[76] Zhen H, et al.. VitA or VitD ameliorates bronchopulmonary dysplasia by regulating the balance between M1 and M2 macrophages. Biomed. Pharmacother., 2021, 141 111836

[77] Orning P, et al.. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science, 2018, 362: 1064-1069

[78] Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ., 2003, 10: 45-65

[79] Shi J, et al.. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 2015, 526: 660-665

[80] Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat. Rev. Immunol., 2018, 18: 773-789

[81] Sims NA, Lévesque JP. Oncostatin M: dual regulator of the skeletal and hematopoietic systems. Curr. Osteoporos. Rep., 2024, 22: 80-95

[82] Zhao X, Chen J, Sun H, Zhang Y, Zou D. New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP-ECM interaction. Cell Biosci., 2022, 12: 117

[83] Van den Steen PE, Proost P, Wuyts A, Van Damme J, Opdenakker G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood, 2000, 96: 2673-2681

[84] Dai X, et al.. Dihydroartemisinin inhibits the development of colorectal cancer by GSK-3β/TCF7/MMP9 pathway and synergies with capecitabine. Cancer Lett., 2024, 582 216596

[85] Schilperoort M, et al.. The role of efferocytosis-fueled macrophage metabolism in the resolution of inflammation. Immunol. Rev., 2023, 319: 65-80

[86] Graney PL, et al.. Macrophages of diverse phenotypes drive vascularization of engineered tissues. Sci. Adv., 2020, 6 eaay6391

[87] Yan L, et al.. Macrophage plasticity: signaling pathways, tissue repair, and regeneration. MedComm, 2024, 5 e658

[88] Mishra B, et al.. IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms. Nat. Immunol., 2025, 26: 748-759

[89] Deng Z, et al.. TGF-β signaling in health, disease, and therapeutics. Signal Transduct. Target. Ther., 2024, 9: 61

[90] Khalilzad MA, et al.. Therapeutic potential of apoptotic vesicles in modulating inflammation, immune responses, and tissue regeneration. J. Nanobiotechnology, 2025, 23 260

[91] Gao Y, et al.. Transfer of inflammatory mitochondria via extracellular vesicles from M1 macrophages induces ferroptosis of pancreatic beta cells in acute pancreatitis. J. Extracell. Vesicles, 2024, 13 e12410

[92] Sun Z, et al.. Pak4-mediated crosstalk between necroptotic macrophages and tendon stem/progenitor cells contributes to traumatic heterotopic ossification formation. Bone Res., 2025, 13: 88

[93] Zhang C, et al.. Engineered extracellular vesicles derived from primary M2 macrophages with anti-inflammatory and neuroprotective properties for the treatment of spinal cord injury. J. Nanobiotechnology, 2021, 19 373

[94] Hua F, et al.. Macrophage-derived extracellular vesicles transfer mitochondria to adipocytes and promote adipocyte-myofibroblast transition in epidural fibrosis. npj Regen. Med., 2024, 9: 43

[95] Xu C, et al.. Small extracellular vesicle-mediated miR-320e transmission promotes osteogenesis in OPLL by targeting TAK1. Nat. Commun., 2022, 13 2467

[96] Chi Z, et al.. Gasdermin D-mediated metabolic crosstalk promotes tissue repair. Nature, 2024, 634: 1168-1177

[97] Medzhitov R. The spectrum of inflammatory responses. Science, 2021, 374: 1070-1075

[98] Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity, 2016, 44: 450-462

[99] Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med., 2012, 18: 1028-1040

[100] Han H, et al.. Macrophage-derived osteopontin (SPP1) protects from nonalcoholic steatohepatitis. Gastroenterology, 2023, 165: 201-217

[101] Nichols AEC, Best KT, Loiselle AE. The cellular basis of fibrotic tendon healing: challenges and opportunities. Transl. Res., 2019, 209: 156-168

[102] Endo T, et al.. Ossification of the posterior longitudinal ligament is linked to heterotopic ossification of the ankle/foot tendons. J. Bone Miner. Metab., 2024, 42: 538-550

[103] Zhang X, et al.. Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration. Bone Res., 2024, 12: 27

[104] Cieri MB, Ramos AJ. Astrocytes, reactive astrogliosis, and glial scar formation in traumatic brain injury. Neural Regen. Res., 2025, 20: 973-989

[105] Bradbury EJ, Burnside ER. Moving beyond the glial scar for spinal cord repair. Nat. Commun., 2019, 10 3879

[106] Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol., 2014, 15: 786-801

[107] Sutherland TE, Dyer DP, Allen JE. The extracellular matrix and the immune system: a mutually dependent relationship. Science, 2023, 379 eabp8964

[108] Bhattacharya DS, et al.. Sulfation modulates the targeting properties of hyaluronic acid to P-selectin and CD44. ACS Biomater. Sci. Eng., 2020, 6: 3585-3598

[109] Lim HY, et al.. Hyaluronan receptor LYVE-1-expressing macrophages maintain arterial tone through hyaluronan-mediated regulation of smooth muscle cell collagen. Immunity, 2018, 49: 326-341.e7

[110] Du H, et al.. Tuning immunity through tissue mechanotransduction. Nat. Rev. Immunol., 2023, 23: 174-188

[111] Madsen DH, et al.. Tumor-associated macrophages derived from circulating inflammatory monocytes degrade collagen through cellular uptake. Cell Rep., 2017, 21: 3662-3671

[112] Yu J, et al.. Tumor-associated macrophages depend on MMP1 for their cancer-promoting role. Cell Death Discov., 2021, 7: 343

[113] Huang X, et al.. Vimentin intermediate filaments coordinate actin stress fibers and podosomes to determine extracellular matrix degradation by macrophages. Dev. Cell, 2025, 60: 1669-1685.e6

[114] Zou H, et al.. LINC01089 governs the miR-1287-5p/HSPA4 axis to negatively regulate osteogenic differentiation of mesenchymal stem cells. Bone Jt. Res., 2024, 13: 779-789

[115] Terkawi MA, et al.. Interplay between inflammation and pathological bone resorption: insights into recent mechanisms and pathways in related diseases for future perspectives. Int. J. Mol. Sci., 2022, 23: 1786

[116] Vallés G, et al.. Influence of inflammatory conditions provided by macrophages on osteogenic ability of mesenchymal stem cells. Stem Cell Res. Ther., 2020, 11: 57

[117] Guihard P, et al.. Induction of osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling. Stem Cells, 2012, 30: 762-772

[118] Liu S, et al.. Erythropoietin-stimulated macrophage-derived extracellular vesicles in chitosan hydrogel rescue BMSCs fate by targeting EGFR to alleviate inflammatory bone loss in periodontitis. Adv. Sci., 2025, 12 e2500554

[119] Németh K, et al.. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med., 2009, 15: 42-49

[120] Lin WT, et al.. Modulation of experimental acute lung injury by exosomal miR-7704 from mesenchymal stromal cells acts through M2 macrophage polarization. Mol. Ther. Nucleic Acids, 2023, 35 102102

[121] Zheng X, et al.. Effect of micro/nano-sheet array structures on the osteo-immunomodulation of macrophages. Regen. Biomater., 2022, 9 rbac075

[122] Dupont S, et al.. Role of YAP/TAZ in mechanotransduction. Nature, 2011, 474: 179-183

[123] Meizlish ML, et al.. Mechanosensing regulates tissue repair program in macrophages. Sci. Adv., 2024, 10 eadk6906

[124] Osta B, Benedetti G, Miossec P. Classical and paradoxical effects of TNF-α on bone homeostasis. Front. Immunol., 2014, 5: 48

[125] Braun T, Schett G. Pathways for bone loss in inflammatory disease. Curr. Osteoporos. Rep., 2012, 10: 101-108

[126] Kavadichanda CG, Geng J, Bulusu SN, Negi VS, Raghavan M. Spondyloarthritis and the human leukocyte antigen (HLA)-B*27 connection. Front. Immunol., 2021, 12 601518

[127] Coury F, Peyruchaud O, Machuca-Gayet I. Osteoimmunology of bone loss in inflammatory rheumatic diseases. Front. Immunol., 2019, 10: 679

[128] Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat. Rev. Rheumatol., 2012, 8: 656-664

[129] Cambré I, et al.. Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. Nat. Commun., 2018, 9 4613

[130] Kaaij MH, et al.. Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis. J. Exp. Med., 2020, 217 e20200288

[131] Schett G, Coates LC, Ash ZR, Finzel S, Conaghan PG. Structural damage in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: traditional views, novel insights gained from TNF blockade, and concepts for the future. Arthritis Res. Ther., 2011, 13 S4

[132] Killian ML. Growth and mechanobiology of the tendon-bone enthesis. Semin. Cell Dev. Biol., 2022, 123: 64-73

[133] Jacques P, et al.. Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann. Rheum. Dis., 2014, 73: 437-445

[134] Zhang Y, Feng X, Zheng B, Liu Y. Regulation and mechanistic insights into tensile strain in mesenchymal stem cell osteogenic differentiation. Bone, 2024, 187 117197

[135] Wu X, et al.. Mechanism of cyclic tensile stress in osteogenic differentiation of human periodontal ligament stem cells. Calcif. Tissue Int., 2021, 108: 640-653

[136] Chen S, et al.. Piezo1-mediated mechanotransduction promotes entheseal pathological new bone formation in ankylosing spondylitis. Ann. Rheum. Dis., 2023, 82: 533-545

[137] Singh N, Trajkovski A, Trajkovski J, Kunc R, Matas JFR. A pilot study on the age-dependent, biomechanical properties of longitudinal ligaments in the human cervical spine. Bioengineering, 2025, 12: 61

[138] Kim E, et al.. YAP mechanotransduction under cyclic mechanical stretch loading for mesenchymal stem cell osteogenesis is regulated by ROCK. Front. Bioeng. Biotechnol., 2024, 11 1306002

[139] Cutolo M, Soldano S, Smith V, Gotelli E, Hysa E. Dynamic macrophage phenotypes in autoimmune and inflammatory rheumatic diseases. Nat. Rev. Rheumatol., 2025, 21: 546-565

[140] Li J, et al.. Targeting macrophage M1 polarization suppression through PCAF inhibition alleviates autoimmune arthritis via synergistic NF-κB and H3K9Ac blockade. J. Nanobiotechnology, 2023, 21 280

[141] Sun XG, et al.. Aerobic glycolysis induced by mTOR/HIF-1α promotes early brain injury after subarachnoid hemorrhage via activating M1 microglia. Transl. Stroke Res., 2024, 15: 1-15

[142] Byles V, et al.. The TSC-mTOR pathway regulates macrophage polarization. Nat. Commun., 2013, 4 2834

[143] Sag D, Carling D, Stout RD, Suttles J. Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol., 2008, 181: 8633-8641

[144] Postler TS, Peng V, Bhatt DM, Ghosh S. Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism. Sci. Rep., 2021, 11 18721

[145] Odegaard JI, et al.. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature, 2007, 447: 1116-1120

[146] Guo Q, et al.. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct. Target. Ther., 2024, 9: 53

[147] De Bosscher K, Vanden Berghe W, Haegeman G. The interplay between the glucocorticoid receptor and nuclear factor-κB or activator protein-1: molecular mechanisms for gene repression. Endocr. Rev., 2003, 24: 488-522

[148] Cassetta L, Pollard JW. A timeline of tumour-associated macrophage biology. Nat. Rev. Cancer, 2023, 23: 238-257

[149] Mancuso R, et al.. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain, 2019, 142: 3243-3264

[150] Yang H, et al.. CCL2–CCR2 axis recruits tumor-associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol. Cancer, 2020, 19 41

[151] Han X, et al.. Hexapeptide induces M2 macrophage polarization via the JAK1/STAT6 pathway to promote angiogenesis in bone repair. Exp. Cell Res., 2022, 413 113064

[152] Wang H, Wang X, Zhang Q, Liang Y, Wu H. Matrine reduces traumatic heterotopic ossification in mice by inhibiting M2 macrophage polarization through the MAPK pathway. Biomed. Pharmacother., 2024, 177 117130

[153] Hatsell SJ, et al.. ACVR1 R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci. Transl. Med., 2015, 7: 303ra137

[154] Wang YF, et al.. Aspirin triggers ferroptosis in hepatocellular carcinoma cells through restricting NF-κB p65-activated SLC7A11 transcription. Acta Pharmacol. Sin., 2023, 44: 1712-1724

[155] Li L, et al.. Muscle injury promotes heterotopic ossification by stimulating local bone morphogenetic protein-7 production. J. Orthop. Transl., 2019, 18: 142-153

[156] Majeed M, et al.. A scientifically validated combination of garcinol, curcuminoids, and piperine for mild to moderate nonalcoholic steatohepatitis patients: results from a randomized, double-blind, placebo-controlled study. Front. Nutr., 2023, 10 1201186

[157] Greenberg B, et al.. Phase 1 study of AAV9.LAMP2B gene therapy in Danon disease. N. Engl. J. Med., 2025, 392: 972-983

[158] Pan F, et al.. Metformin for knee osteoarthritis in patients with overweight or obesity: a randomized clinical trial. JAMA, 2025, 333: 1804-1812

[159] Engert LC, et al.. Effects of low-dose acetylsalicylic acid on the inflammatory response to experimental sleep restriction in healthy humans. Brain Behav. Immun., 2024, 121: 142-154

[160] Sonneveld P, et al.. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med., 2024, 390: 301-313

[161] Lynch K, et al.. Regulating immunogenicity and tolerogenicity of bone marrow-derived dendritic cells through modulation of cell surface glycosylation by dexamethasone treatment. Front. Immunol., 2017, 8: 1427

[162] Llovet JM, et al.. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med., 2008, 359: 378-390

[163] Lu LG, et al.. Oxymatrine therapy for chronic hepatitis B: a randomized double-blind and placebo-controlled multi-center trial. World J. Gastroenterol., 2003, 9: 2480-2483

[164] Di Rocco M, et al.. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial. Nat. Med., 2023, 29: 2615-2624

[165] Genovese MC, et al.. Results from a phase IIA parallel group study of JNJ-40346527, an oral CSF-1R inhibitor, in patients with active rheumatoid arthritis despite disease-modifying antirheumatic drug therapy. J. Rheumatol., 2015, 42: 1752-1760

[166] Wagner DE, et al.. Inhibition of epithelial cell YAP–TEAD/LOX signaling attenuates pulmonary fibrosis in preclinical models. Nat. Commun., 2025, 16 7099

[167] Hanada Y, et al.. EUS-guided verteporfin photodynamic therapy for pancreatic cancer. Gastrointest. Endosc., 2021, 94: 179-186

Rights & permissions

The Author(s)