Intervertebral disc degeneration (IDD) and osteoarthritis (OA) affecting the facet joint of the spine are biomechanically interdependent, typically occur in tandem, and have considerable epidemiological and pathophysiological overlap. Historically, the distinctions between these degenerative diseases have been emphasized. Therefore, research in the two fields often occurs independently without adequate consideration of the co-dependence of the two sites, which reside within the same functional spinal unit. Emerging evidence from animal models of spine degeneration highlight the interdependence of IDD and facet joint OA, warranting a review of the parallels between these two degenerative phenomena for the benefit of both clinicians and research scientists. This Review discusses the pathophysiological aspects of IDD and OA, with an emphasis on tissue, cellular and molecular pathways of degeneration. Although the intervertebral disc and synovial facet joint are biologically distinct structures that are amenable to reductive scientific consideration, substantial overlap exists between the molecular pathways and processes of degeneration (including cartilage destruction, extracellular matrix degeneration and osteophyte formation) that occur at these sites. Thus, researchers, clinicians, advocates and policy-makers should consider viewing the burden and management of spinal degeneration holistically as part of the OA disease continuum.
Each functional spinal unit is made up of two vertebrae, one fibrocartilaginous intervertebral disc (IVD) joint and two conventional synovial facet joints.
Phenomenological features of IVD degeneration and facet joint osteoarthritis have considerable overlap, including the destruction of cartilage and other joint tissues, subchondral bone changes, osteophyte formation and reduced joint space.
Important overlapping endogenous molecular processes of IVD degeneration and facet joint osteoarthritis include extracellular matrix degeneration, inflammation, oxidative stress, apoptosis, senescence and reduced autophagy.
An important objective for the field will be to determine whether unique clinically relevant overlapping endotypes are present, which might correspond to a specific molecular process or biomarker.
Further unified studies are required that directly compare the molecular signatures of matched tissue samples from the IVD and facet joint using clinical samples and/or mouse models of disease progression.
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Lo, J., Chan, L. & Flynn, S. A Systematic review of the incidence, prevalence, costs, and activity and work limitations of amputation, osteoarthritis, rheumatoid arthritis, back pain, multiple sclerosis, spinal cord injury, stroke, and traumatic brain injury in the United States: a 2019 update. Arch. Phys. Med. Rehabil. 102, 115–131 (2021).
Allen, K. D., Thoma, L. M. & Golightly, Y. M. Epidemiology of osteoarthritis. Osteoarthr. Cartil. 30, 184–195 (2022).
Hartvigsen, J. et al. What low back pain is and why we need to pay attention. Lancet 391, 2356–2367 (2018).
Institute for Health Metrics and Evaluation (IHME). Low back pain — level 3 cause. https://www.healthdata.org/results/gbd_summaries/2019/low-back-pain-level-3-cause (IHME, University of Washington, 2020).
Manchikanti, L. & Singh, V. Review of chronic low back pain of facet joint origin. Pain Physician 5, 83–101 (2002).
Luoma, K. et al. Low back pain in relation to lumbar disc degeneration. Spine 25, 487–492 (2000).
Perolat, R. et al. Facet joint syndrome: from diagnosis to interventional management. Insights Imaging 9, 773–789 (2018).
Yamashita, K. et al. Accurate diagnosis of low back pain in adult elite athletes. J. Med. Invest. 66, 252–257 (2019).
Rahyussalim, A. J., Zufar, M. L. L. & Kurniawati, T. Significance of the association between disc degeneration changes on imaging and low back pain: a review article. Asian Spine J. 14, 245–257 (2020).
Paholpak, P. et al. Do modic changes, disc degeneration, translation and angular motion affect facet osteoarthritis of the lumbar spine. Eur. J. Radiol. 98, 193–199 (2018).
Kirkaldy-Willis, W. H. & Farfan, H. F. Instability of the lumbar spine. Clin. Orthop. Relat. Res. 165, 110–123 (1982).
Eubanks, J. D., Lee, M. J., Cassinelli, E. & Ahn, N. U. Does lumbar facet arthrosis precede disc degeneration? A postmortem study. Clin. Orthop. Relat. Res. 464, 184–189 (2007).
Kushchayev, S. V. et al. ABCs of the degenerative spine. Insights Imaging 9, 253–274 (2018).
Li, J., Muehleman, C., Abe, Y. & Masuda, K. Prevalence of facet joint degeneration in association with intervertebral joint degeneration in a sample of organ donors. J. Orthop. Res. 29, 1267–1274 (2011).
Suri, P. et al. Does lumbar spinal degeneration begin with the anterior structures? A study of the observed epidemiology in a community-based population. BMC Musculoskelet. Disord. 12, 202 (2011).
Nelson, A. E., Smith, M. W., Golightly, Y. M. & Jordan, J. M. “Generalized osteoarthritis”: a systematic review. Semin. Arthritis Rheum. 43, 713–720 (2014).
Goode, A. P. et al. Lumbar spine radiographic features and demographic, clinical, and radiographic knee, hip, and hand osteoarthritis. Arthritis Care Res. 64, 1536–1544 (2012).
Perruccio, A. V. et al. The impact of multijoint symptoms on patient-reported disability following surgery for lumbar spine osteoarthritis. Spine J. 21, 80–89 (2021).
Grignon, B. & Roland, J. Can the human intervertebral disc be compared to a diarthrodial joint? Surg. Radiol. Anat. 22, 101–105 (2000).
Gellhorn, A. C., Katz, J. N. & Suri, P. Osteoarthritis of the spine: the facet joints. Nat. Rev. Rheumatol. 9, 216–224 (2013).
Lane, N. E. et al. OARSI-FDA initiative: defining the disease state of osteoarthritis. Osteoarthr. Cartil. 19, 478–482 (2011).
Badley, E. M., Millstone, D. B. & Perruccio, A. V. Back pain and co-occurring conditions: findings from a nationally representative sample. Spine 43, E935–e941 (2018).
Slater, M., Perruccio, A. V. & Badley, E. M. Musculoskeletal comorbidities in cardiovascular disease, diabetes and respiratory disease: the impact on activity limitations; a representative population-based study. BMC Public Health 11, 77 (2011).
Swain, S., Sarmanova, A., Coupland, C., Doherty, M. & Zhang, W. Comorbidities in osteoarthritis: a systematic review and meta-analysis of observational studies. Arthritis Care Res. 72, 991–1000 (2020).
Constantino de Campos, G. et al. Osteoarthritis, mobility-related comorbidities and mortality: an overview of meta-analyses. Ther. Adv. Musculoskelet. Dis. 12, 1759720x20981219 (2020).
Roseen, E. J. et al. Association of back pain with mortality: a systematic review and meta-analysis of cohort studies. J. Gen. Intern. Med. 36, 3148–3158 (2021).
Rustenburg, C. M. E. et al. Osteoarthritis and intervertebral disc degeneration: quite different, quite similar. JOR Spine 1, e1033 (2018).
Collins, D. H. The Pathology of Articular and Spinal Disease 74–115 (Edward Arnold & Co, 1949).
Oegema, T. R. Jr. & Bradford, D. S. The inter-relationship of facet joint osteoarthritis and degenerative disc disease. Br. J. Rheumatol. 30 (Suppl. 1), 16–20 (1991).
Fujiwara, A. et al. The relationship between disc degeneration, facet joint osteoarthritis, and stability of the degenerative lumbar spine. J. Spinal Disord. 13, 444–450 (2000).
Adams, M. A. & Roughley, P. J. What is intervertebral disc degeneration, and what causes it? Spine 31, 2151–2161 (2006).
de Luca, K. et al. Consensus for statements regarding a definition for spinal osteoarthritis for use in research and clinical practice: a Delphi study. Arthritis Care Res. https://doi.org/10.1002/acr.24829 (2021).
Bogduk, N. Clinical and Radiological Anatomy of the Lumbar Spine 5th edn (Churchill Livingstone Elsevier, 2012).
Huang, Y. C., Urban, J. P. & Luk, K. D. Intervertebral disc regeneration: do nutrients lead the way. Nat. Rev. Rheumatol. 10, 561–566 (2014).
Rivera Tapia, E. D., Meakin, J. R. & Holsgrove, T. P. In-vitro models of disc degeneration — a review of methods and clinical relevance. J. Biomech. 142, 111260 (2022).
Fearing, B. V., Hernandez, P. A., Setton, L. A. & Chahine, N. O. Mechanotransduction and cell biomechanics of the intervertebral disc. JOR Spine https://doi.org/10.1002/jsp2.1026 (2018).
Wong, J. et al. Nutrient supply and nucleus pulposus cell function: effects of the transport properties of the cartilage endplate and potential implications for intradiscal biologic therapy. Osteoarthr. Cartil. 27, 956–964 (2019).
Tomaszewski, K. A., Saganiak, K., Gładysz, T. & Walocha, J. A. The biology behind the human intervertebral disc and its endplates. Folia Morphol. 74, 157–168 (2015).
Kapetanakis, S. & Gkantsinikoudis, N. Anatomy of lumbar facet joint: a comprehensive review. Folia Morphol. 80, 799–805 (2021).
Almeer, G. et al. Anatomy and pathology of facet joint. J. Orthop. 22, 109–117 (2020).
Ko, H.-Y. in Management and Rehabilitation of Spinal Cord Injuries (ed. Hyun-Yoon Ko) 101–114 (Springer Nature Singapore, 2022).
Monemdjou, R., Fahmi, H. & Kapoor, M. Synovium in the pathophysiology of osteoarthritis. Therapy 7, 661–668 (2010).
Mathiessen, A. & Conaghan, P. G. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res. Ther. 19, 18 (2017).
Haubruck, P., Pinto, M. M., Moradi, B., Little, C. B. & Gentek, R. Monocytes, macrophages, and their potential niches in synovial joints — therapeutic targets in post-traumatic osteoarthritis? Front. Immunol. 12, 763702 (2021).
Roughley, P. J. & Mort, J. S. The role of aggrecan in normal and osteoarthritic cartilage. J. Exp. Orthop. 1, 8 (2014).
Sophia Fox, A. J., Bedi, A. & Rodeo, S. A. The basic science of articular cartilage: structure, composition, and function. Sports Health 1, 461–468 (2009).
Akkiraju, H. & Nohe, A. Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration. J. Dev. Biol. 3, 177–192 (2015).
Eschweiler, J. et al. The biomechanics of cartilage — an overview. Life 11, 302 (2021).
Das Gupta, S., Workman, J., Finnilä, M. A. J., Saarakkala, S. & Thambyah, A. Subchondral bone plate thickness is associated with micromechanical and microstructural changes in the bovine patella osteochondral junction with different levels of cartilage degeneration. J. Mech. Behav. Biomed. Mater. 129, 105158 (2022).
Fournier, D. E., Kiser, P. K., Shoemaker, J. K., Battié, M. C. & Séguin, C. A. Vascularization of the human intervertebral disc: a scoping review. JOR Spine 3, e1123 (2020).
Adams, M. A., McNally, D. S. & Dolan, P. ‘Stress’ distributions inside intervertebral discs. The effects of age and degeneration. J. Bone Jt. Surg. Br. 78, 965–972 (1996).
Neidlinger-Wilke, C. et al. Mechanical loading of the intervertebral disc: from the macroscopic to the cellular level. Eur. Spine J. 23 (Suppl. 3), 333–343 (2014).
Wang, Y. et al. Hydrostatic pressure modulates intervertebral disc cell survival and extracellular matrix homeostasis via regulating hippo-YAP/TAZ pathway. Stem Cell Int. 2021, 5626487 (2021).
Inoue, N., Orías, A. A. E. & Segami, K. Biomechanics of the lumbar facet joint. Spine Surg. Relat. Res. 4, 1–7 (2020).
Tamer, T. M. Hyaluronan and synovial joint: function, distribution and healing. Interdiscip. Toxicol. 6, 111–125 (2013).
Kirnaz, S. et al. Pathomechanism and biomechanics of degenerative disc disease: features of healthy and degenerated discs. Int. J. Spine Surg. 15, 10–25 (2021).
Kalichman, L. & Hunter, D. J. Lumbar facet joint osteoarthritis: a review. Semin. Arthritis Rheum. 37, 69–80 (2007).
Sebro, R., O’Brien, L., Torriani, M. & Bredella, M. A. Assessment of trunk muscle density using CT and its association with degenerative disc and facet joint disease of the lumbar spine. Skelet. Radiol. 45, 1221–1226 (2016).
Noonan, A. M. & Brown, S. H. M. Paraspinal muscle pathophysiology associated with low back pain and spine degenerative disorders. JOR Spine 4, e1171 (2021).
Elder, B. D. & Athanasiou, K. A. Hydrostatic pressure in articular cartilage tissue engineering: from chondrocytes to tissue regeneration. Tissue Eng. Part B Rev. 15, 43–53 (2009).
Ateshian, G. A. The role of interstitial fluid pressurization in articular cartilage lubrication. J. Biomech. 42, 1163–1176 (2009).
Lambrechts, M. J. et al. Lumbar spine intervertebral disc desiccation is associated with medical comorbidities linked to systemic inflammation. Arch. Orthop. Trauma. Surg. https://doi.org/10.1007/s00402-021-04194-3 (2021).
Videman, T. et al. Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing. Arthritis Rheum. 60, 470–481 (2009).
Ashberg, L. et al. The hip-spine connection: how to differentiate hip conditions from spine pathology. Orthopedics 44, e699–e706 (2021).
Oshima, Y. et al. Knee-hip-spine syndrome: improvement in preoperative abnormal posture following total knee arthroplasty. Adv. Orthopedics 2019, 8484938 (2019).
Hassett, G., Hart, D. J., Doyle, D. V., March, L. & Spector, T. D. The relation between progressive osteoarthritis of the knee and long term progression of osteoarthritis of the hand, hip, and lumbar spine. Ann. Rheum. Dis. 65, 623–628 (2006).
Jentzsch, T. et al. Increased pelvic incidence may lead to arthritis and sagittal orientation of the facet joints at the lower lumbar spine. BMC Med. Imaging 13, 34 (2013).
Roussouly, P. & Pinheiro-Franco, J. L. Biomechanical analysis of the spino-pelvic organization and adaptation in pathology. Eur. Spine J. 20 (Suppl. 5), 609–618 (2011).
Toy, J. O., Tinley, J. C., Eubanks, J. D., Qureshi, S. A. & Ahn, N. U. Correlation of sacropelvic geometry with disc degeneration in spondylolytic cadaver specimens. Spine 37, E10–E15 (2012).
Cacciola, G. et al. High values of pelvic incidence: a possible risk factor for zigoapophyseal facet arthrosis in young. J. Orthop. 15, 333–336 (2018).
Chen, S. Q. et al. Different spinal subtypes with varying characteristics of lumbar disc degeneration at specific level with age: a study based on an asymptomatic population. J. Orthopaed. Surg. Res. 15, 3 (2020).
Cooke, T. D. Static knee alignment and its association with radiographic knee osteoarthritis. Osteoarthr. Cartil. 15, 844–845 (2007).
Bashkuev, M., Reitmaier, S. & Schmidt, H. Relationship between intervertebral disc and facet joint degeneration: a probabilistic finite element model study. J. Biomech. 102, 109518 (2020).
Liu, L. et al. Molecular imaging of collagen destruction of the spine. ACS Nano 15, 19138–19149 (2021).
Fields, A. J., Ballatori, A., Liebenberg, E. C. & Lotz, J. C. Contribution of the endplates to disc degeneration. Curr. Mol. Biol. Rep. 4, 151–160 (2018).
Hassan, C. R., Lee, W., Komatsu, D. E. & Qin, Y. X. Evaluation of nucleus pulposus fluid velocity and pressure alteration induced by cartilage endplate sclerosis using a poro-elastic finite element analysis. Biomech. Modeling Mechanobiol. 20, 281–291 (2021).
Mapp, P. I. & Walsh, D. A. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat. Rev. Rheumatol. 8, 390–398 (2012).
Madry, H., van Dijk, C. N. & Mueller-Gerbl, M. The basic science of the subchondral bone. Knee Surg. Sports Traumatol. Arthrosc. 18, 419–433 (2010).
Ni, R., Guo, X. E., Yan, C. & Wen, C. Hemodynamic stress shapes subchondral bone in osteoarthritis: an emerging hypothesis. J. Orthop. Transl. 32, 85–90 (2022).
Burr, D. B. & Gallant, M. A. Bone remodelling in osteoarthritis. Nat. Rev. Rheumatol. 8, 665–673 (2012).
Donell, S. Subchondral bone remodelling in osteoarthritis. EFORT Open Rev. 4, 221–229 (2019).
Rutges, J. P. H. J. et al. Micro-CT quantification of subchondral endplate changes in intervertebral disc degeneration. Osteoarthr. Cartil. 19, 89–95 (2011).
Fields, A. J., Liebenberg, E. C. & Lotz, J. C. Innervation of pathologies in the lumbar vertebral end plate and intervertebral disc. Spine J. 14, 513–521 (2014).
Torkki, M. et al. Osteoclast activators are elevated in intervertebral disks with Modic changes among patients operated for herniated nucleus pulposus. Eur. Spine J. 25, 207–216 (2016).
Pérez-Lozano, M. L. et al. Gremlin-1 and BMP-4 overexpressed in osteoarthritis drive an osteochondral-remodeling program in osteoblasts and hypertrophic chondrocytes. Int. J. Mol. Sci. https://doi.org/10.3390/ijms23042084 (2022).
Chou, C. H. et al. Synovial cell cross-talk with cartilage plays a major role in the pathogenesis of osteoarthritis. Sci. Rep. 10, 10868 (2020).
Gilbert, S. J., Bonnet, C. S. & Blain, E. J. Mechanical cues: bidirectional reciprocity in the extracellular matrix drives mechano-signalling in articular cartilage. Int. J. Mol. Sci. https://doi.org/10.3390/ijms222413595 (2021).
Veras, M. A., McCann, M. R., Tenn, N. A. & Séguin, C. A. Transcriptional profiling of the murine intervertebral disc and age-associated changes in the nucleus pulposus. Connect. Tissue Res. 61, 63–81 (2020).
McCann, M. R. & Séguin, C. A. Notochord cells in intervertebral disc development and degeneration. J. Dev. Biol. https://doi.org/10.3390/jdb4010003 (2016).
Sivakamasundari, V. & Lufkin, T. Bridging the gap: understanding embryonic intervertebral disc development. Cell Dev. Biol. 1, 103 (2012).
Séguin, C. A., Chan, D., Dahia, C. L. & Gazit, Z. Latest advances in intervertebral disc development and progenitor cells. JOR Spine 1, e1030 (2018).
Torre, O. M., Mroz, V., Bartelstein, M. K., Huang, A. H. & Iatridis, J. C. Annulus fibrosus cell phenotypes in homeostasis and injury: implications for regenerative strategies. Ann. N. Y. Acad. Sci. 1442, 61–78 (2019).
Ding, F., Shao, Z.-W. & Xiong, L.-M. Cell death in intervertebral disc degeneration. Apoptosis 18, 777–785 (2013).
Hwang, H. S. & Kim, H. A. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int. J. Mol. Sci. 16, 26035–26054 (2015).
Nakamura, A. et al. Identification of microRNA-181a-5p and microRNA-4454 as mediators of facet cartilage degeneration. JCI Insight 1, e86820 (2016).
Wang, Y. et al. The role of IL-1β and TNF-α in intervertebral disc degeneration. Biomed. Pharmacother. 131, 110660 (2020).
Estrada McDermott, J. et al. Role of innate immunity in initiation and progression of osteoarthritis, with emphasis on horses. Animals https://doi.org/10.3390/ani11113247 (2021).
Nakazawa, K. R. et al. Accumulation and localization of macrophage phenotypes with human intervertebral disc degeneration. Spine J. 18, 343–356 (2018).
Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).
Fahy, N. et al. Human osteoarthritic synovium impacts chondrogenic differentiation of mesenchymal stem cells via macrophage polarisation state. Osteoarthr. Cartil. 22, 1167–1175 (2014).
Liu, B., Zhang, M., Zhao, J., Zheng, M. & Yang, H. Imbalance of M1/M2 macrophages is linked to severity level of knee osteoarthritis. Exp. Ther. Med. 16, 5009–5014 (2018).
Tsuneyoshi, Y. et al. Functional folate receptor beta-expressing macrophages in osteoarthritis synovium and their M1/M2 expression profiles. Scand. J. Rheumatol. 41, 132–140 (2012).
Wu, C. L. et al. Conditional macrophage depletion increases inflammation and does not inhibit the development of osteoarthritis in obese macrophage fas-induced apoptosis-transgenic mice. Arthritis Rheumatol. 69, 1772–1783 (2017).
Kawakubo, A. et al. Investigation of resident and recruited macrophages following disc injury in mice. J. Orthopaed. Res. 38, 1703–1709 (2020).
Miyagi, M. et al. Macrophage-derived inflammatory cytokines regulate growth factors and pain-related molecules in mice with intervertebral disc injury. J. Orthopaed. Res. https://doi.org/10.1002/jor.23888 (2018).
Yamagishi, A., Nakajima, H., Kokubo, Y., Yamamoto, Y. & Matsumine, A. Polarization of infiltrating macrophages in the outer annulus fibrosus layer associated with the process of intervertebral disc degeneration and neural ingrowth in the human cervical spine. Spine J. https://doi.org/10.1016/j.spinee.2021.12.005 (2021).
Laskin, D. L., Sunil, V. R., Gardner, C. R. & Laskin, J. D. Macrophages and tissue injury: agents of defense or destruction. Annu. Rev. Pharmacol. Toxicol. 51, 267–288 (2011).
Culemann, S. et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature 572, 670–675 (2019).
Mobasheri, A. et al. Recent advances in understanding the phenotypes of osteoarthritis. F1000Research https://doi.org/10.12688/f1000research.20575.1 (2019).
Knobloch, T. J., Madhavan, S., Nam, J., Agarwal, S. Jr. & Agarwal, S. Regulation of chondrocytic gene expression by biomechanical signals. Crit. Rev. Eukaryot. Gene Expr. 18, 139–150 (2008).
Bleuel, J., Zaucke, F., Brüggemann, G. P. & Niehoff, A. Effects of cyclic tensile strain on chondrocyte metabolism: a systematic review. PLoS One 10, e0119816 (2015).
Belavý, D. L. et al. Running exercise strengthens the intervertebral disc. Sci. Rep. 7, 45975 (2017).
Fransen, M. et al. Exercise for osteoarthritis of the knee: a Cochrane systematic review. Br. J. Sports Med. 49, 1554 (2015).
Li, Z. et al. Moderate-intensity exercise alleviates pyroptosis by promoting autophagy in osteoarthritis via the P2X7/AMPK/mTOR axis. Cell Death Discov. 7, 346 (2021).
Vo, N. V. et al. Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration. Spine J. 13, 331–341 (2013).
Tetlow, L. C., Adlam, D. J. & Woolley, D. E. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum. 44, 585–594 (2001).
Ohnishi, T., Novais, E. J. & Risbud, M. V. Alterations in ECM signature underscore multiple sub-phenotypes of intervertebral disc degeneration. Matrix Biol. 6-7, 100036 (2020).
Maldonado, M. & Nam, J. The role of changes in extracellular matrix of cartilage in the presence of inflammation on the pathology of osteoarthritis. Biomed. Res. Int. 2013, 284873 (2013).
Schuster, R., Rockel, J. S., Kapoor, M. & Hinz, B. The inflammatory speech of fibroblasts. Immunol. Rev. 302, 126–146 (2021).
Wynn, T. A. & Barron, L. Macrophages: master regulators of inflammation and fibrosis. Semin. Liver Dis. 30, 245–257 (2010).
Hou, Y., Shi, G., Guo, Y. & Shi, J. Epigenetic modulation of macrophage polarization prevents lumbar disc degeneration. Aging 12, 6558–6569 (2020).
Chen, S. et al. TGF-β signaling in intervertebral disc health and disease. Osteoarthr. Cartil. 27, 1109–1117 (2019).
Wu, C. L., Harasymowicz, N. S., Klimak, M. A., Collins, K. H. & Guilak, F. The role of macrophages in osteoarthritis and cartilage repair. Osteoarthr. Cartil. 28, 544–554 (2020).
Rim, Y. A. & Ju, J. H. The role of fibrosis in osteoarthritis progression. Life https://doi.org/10.3390/life11010003 (2020).
Maglaviceanu, A., Wu, B. & Kapoor, M. Fibroblast-like synoviocytes: role in synovial fibrosis associated with osteoarthritis. Wound Repair Regen. 29, 642–649 (2021).
Yee, A. et al. Fibrotic-like changes in degenerate human intervertebral discs revealed by quantitative proteomic analysis. Osteoarthr. Cartil. 24, 503–513 (2016).
Au, T. Y. K. et al. Transformation of resident notochord-descendent nucleus pulposus cells in mouse injury-induced fibrotic intervertebral discs. Aging Cell 19, e13254 (2020).
Lotz, M. K. & Caramés, B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat. Rev. Rheumatol. 7, 579–587 (2011).
Rockel, J. S. & Kapoor, M. Autophagy: controlling cell fate in rheumatic diseases. Nat. Rev. Rheumatol. 12, 517–531 (2016).
Madhu, V., Guntur, A. R. & Risbud, M. V. Role of autophagy in intervertebral disc and cartilage function: implications in health and disease. Matrix Biol. 100-101, 207–220 (2021).
Kritschil, R., Scott, M., Sowa, G. & Vo, N. Role of autophagy in intervertebral disc degeneration. J. Cell Physiol. 237, 1266–1284 (2022).
Zhang, Y. et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann. Rheum. Dis. 74, 1432–1440 (2015).
Vasheghani, F. et al. PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann. Rheum. Dis. 74, 569–578 (2015).
Kakiuchi, Y. et al. Pharmacological inhibition of mTORC1 but not mTORC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction. Osteoarthr. Cartil. 27, 965–976 (2019).
Feng, C. et al. ROS: Crucial intermediators in the pathogenesis of intervertebral disc degeneration. Oxid. Med. Cell. Longev. 2017, 5601593 (2017).
Liu, Q., Tan, Z., Xie, C., Ling, L. & Hu, H. Oxidative stress as a critical factor might involve in intervertebral disc degeneration via regulating NOXs/FOXOs. J. Orthopaed. Sci. https://doi.org/10.1016/j.jos.2021.09.010 (2021).
Tudorachi, N. B. et al. The implication of reactive oxygen species and antioxidants in knee osteoarthritis. Antioxidants https://doi.org/10.3390/antiox10060985 (2021).
Nasto, L. A. et al. Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration. J. Orthopaed. Res. 31, 1150–1157 (2013).
Koike, M. et al. Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration. Sci. Rep. 5, 11722 (2015).
Fernández-Moreno, M., Rego-Pérez, I. & Blanco, F. J. Is osteoarthritis a mitochondrial disease? What is the evidence. Curr. Opin. Rheumatol. 34, 46–53 (2022).
Molinos, M. et al. Inflammation in intervertebral disc degeneration and regeneration. J. R. Soc. Interface 12, 20141191 (2015).
Lyu, F.-J. et al. Painful intervertebral disc degeneration and inflammation: from laboratory evidence to clinical interventions. Bone Res. 9, 7 (2021).
Sokolove, J. & Lepus, C. M. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther. Adv. Musculoskelet. Dis. 5, 77–94 (2013).
Berenbaum, F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 21, 16–21 (2013).
Scanzello, C. R. Role of low-grade inflammation in osteoarthritis. Curr. Opin. Rheumatol. 29, 79–85 (2017).
Woodell-May, J. E. & Sommerfeld, S. D. Role of inflammation and the immune system in the progression of osteoarthritis. J. Orthopaed. Res. Soc. 38, 253–257 (2020).
Sanchez-Lopez, E., Coras, R., Torres, A., Lane, N. E. & Guma, M. Synovial inflammation in osteoarthritis progression. Nat. Rev. Rheumatol. 18, 258–275 (2022).
Shi, C. et al. MiR-202-3p regulates interleukin-1β-induced expression of matrix metalloproteinase 1 in human nucleus pulposus. Gene 687, 156–165 (2019).
Séguin, C. A., Pilliar, R. M., Roughley, P. J. & Kandel, R. A. Tumor necrosis factorα modulates matrix production and catabolism in nucleus pulposus tissue. Spine 30, 1940–1948 (2005).
Xue, J., Wang, J., Liu, Q. & Luo, A. Tumor necrosis factor-α induces ADAMTS-4 expression in human osteoarthritis chondrocytes. Mol. Med. Rep. 8, 1755–1760 (2013).
Le Maitre, C. L., Hoyland, J. A. & Freemont, A. J. Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1β and TNFα expression profile. Arthritis Res. Ther. 9, R77 (2007).
Chen, Y. et al. Macrophages in osteoarthritis: pathophysiology and therapeutics. Am. J. Transl. Res. 12, 261–268 (2020).
Miller, R. E., Scanzello, C. R. & Malfait, A.-M. An emerging role for Toll-like receptors at the neuroimmune interface in osteoarthritis. Semin. Immunopathol. 41, 583–594 (2019).
Klawitter, M. et al. Expression and regulation of toll-like receptors (TLRs) in human intervertebral disc cells. Eur. Spine J. 23, 1878–1891 (2014).
Sakalyte, R. et al. The expression of inflammasomes NLRP1 and NLRP3, toll-like receptors, and vitamin D receptor in synovial fibroblasts from patients with different types of knee arthritis. Front. Immunol. https://doi.org/10.3389/fimmu.2021.767512 (2022).
Krock, E. et al. Toll-like receptor activation induces degeneration of human intervertebral discs. Sci. Rep. 7, 17184 (2017).
Barreto, G., Manninen, M. & K, K. E. Osteoarthritis and toll-like receptors: when innate immunity meets chondrocyte apoptosis. Biology https://doi.org/10.3390/biology9040065 (2020).
Wang, L. et al. Dioscin attenuates interleukin 1β (IL-1β)-induced catabolism and apoptosis via modulating the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling in human nucleus pulposus cells. Med. Sci. Monit. 26, e923386 (2020).
van Lent, P. L. et al. Crucial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation. Arthritis Rheum. 50, 103–111 (2004).
Zhen, G. & Cao, X. Targeting TGFβ signaling in subchondral bone and articular cartilage homeostasis. Trends Pharmacol. Sci. 35, 227–236 (2014).
Bian, Q. et al. Excessive activation of TGFβ by spinal instability causes vertebral endplate sclerosis. Sci. Rep. 6, 27093 (2016).
Thielen, N. et al. Osteoarthritis-related inflammation blocks TGF-β‘s protective effect on chondrocyte hypertrophy via (de)phosphorylation of the SMAD2/3 linker region. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22158124 (2021).
Yokozeki, Y. et al. TGF-β regulates nerve growth factor expression in a mouse intervertebral disc injury model. BMC Musculoskelet. Disord. 22, 634 (2021).
Francisco, V. et al. A new immunometabolic perspective of intervertebral disc degeneration. Nat. Rev. Rheumatol. 18, 47–60 (2022).
Risbud, M. V. & Shapiro, I. M. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat. Rev. Rheumatol. 10, 44–56 (2014).
Conde, J. et al. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease. Arthritis 2011, 203901 (2011).
Ruiz-Fernández, C. et al. Molecular relationships among obesity, inflammation and intervertebral disc degeneration: are adipokines the common link? Int. J. Mol. Sci. https://doi.org/10.3390/ijms20082030 (2019).
Lai, Q. et al. Expression of adiponectin in the subchondral bone of lumbar facet joints with different degrees of degeneration. BMC Musculoskelet. Disord. 18, 427 (2017).
Zhao, C. W. et al. An update on the emerging role of resistin on the pathogenesis of osteoarthritis. Mediators Inflamm. 2019, 1532164 (2019).
Yan, M., Zhang, J., Yang, H. & Sun, Y. The role of leptin in osteoarthritis. Medicine 97, e0257 (2018).
Hui, W. et al. Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. Ann. Rheum. Dis. 71, 455 (2012).
Francisco, V. et al. Biomechanics, obesity, and osteoarthritis. The role of adipokines: when the levee breaks. J. Orthopaed. Res. 36, 594–604 (2018).
Piva, S. R. et al. Links between osteoarthritis and diabetes: implications for management from a physical activity perspective. Clin. Geriatr. Med. 31, 67–87 (2015).
Laiguillon, M. C. et al. Characterization of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte activation: toward pathophysiological delineation of diabetes mellitus-related osteoarthritis. Osteoarthr. Cartil. 23, 1513–1522 (2015).
Mobasheri, A., Matta, C., Zákány, R. & Musumeci, G. Chondrosenescence: definition, hallmarks and potential role in the pathogenesis of osteoarthritis. Maturitas 80, 237–244 (2015).
Endisha, H., Rockel, J., Jurisica, I. & Kapoor, M. The complex landscape of microRNAs in articular cartilage: biology, pathology, and therapeutic targets. JCI Insight https://doi.org/10.1172/jci.insight.121630 (2018).
Zhao, L. et al. Extensive mechanical tension promotes annulus fibrosus cell senescence through suppressing cellular autophagy. Biosci. Rep. https://doi.org/10.1042/bsr20190163 (2019).
Zhang, Y. et al. Cell senescence: a nonnegligible cell state under survival stress in pathology of intervertebral disc degeneration. Oxid. Med. Cell. Longev. 2020, 9503562 (2020).
Zhang, X.-X. et al. Aging, cell senescence, the pathogenesis and targeted therapies of osteoarthritis. Front. Pharmacol. https://doi.org/10.3389/fphar.2021.728100 (2021).
Zhang, J. et al. Interaction between C/EBPβ and RUNX2 promotes apoptosis of chondrocytes during human lumbar facet joint degeneration. J. Mol. Histol. 51, 401–410 (2020).
Jiang, J. et al. Knockdown of TRAF6 inhibits chondrocytes apoptosis and inflammation by suppressing the NF-κB pathway in lumbar facet joint osteoarthritis. Mol. Cell Biochem. 476, 1929–1938 (2021).
Cazzanelli, P. & Wuertz-Kozak, K. MicroRNAs in intervertebral disc degeneration, apoptosis, inflammation, and mechanobiology. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21103601 (2020).
Malemud, C. J. MicroRNAs and osteoarthritis. Cells https://doi.org/10.3390/cells7080092 (2018).
Ding, Y., Wang, L., Zhao, Q., Wu, Z. & Kong, L. MicroRNA-93 inhibits chondrocyte apoptosis and inflammation in osteoarthritis by targeting the TLR4/NF-κB signaling pathway. Int. J. Mol. Med. 43, 779–790 (2019).
Xin, J. et al. Treatment of intervertebral disc degeneration. Orthopaed. Surg. 14, 1271–1280 (2022).
Civinini, R. et al. Growth factors in the treatment of early osteoarthritis. Clin. Cases Miner. Bone Metab. 10, 26–29 (2013).
Conaghan, P. G., Cook, A. D., Hamilton, J. A. & Tak, P. P. Therapeutic options for targeting inflammatory osteoarthritis pain. Nat. Rev. Rheumatol. 15, 355–363 (2019).
Mohd Isa, I. L. et al. Intervertebral disc degeneration: biomaterials and tissue engineering strategies toward precision medicine. Adv. Healthc. Mater. 11, e2102530 (2022).
Urban, J. P. G. & Fairbank, J. C. T. Current perspectives on the role of biomechanical loading and genetics in development of disc degeneration and low back pain; a narrative review. J. Biomech. 102, 109573 (2020).
Dório, M. & Deveza, L. A. Phenotypes in osteoarthritis: why do we need them and where are we at? Clin. Geriatr. Med. 38, 273–286 (2022).
Arendt-Nielsen, L. et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur. J. Pain. 22, 216–241 (2018).
van Spil, W. E. et al. A consensus-based framework for conducting and reporting osteoarthritis phenotype research. Arthritis Res. Ther. 22, 54 (2020).
Pattappa, G. et al. Diversity of intervertebral disc cells: phenotype and function. J. Anat. 221, 480–496 (2012).
Haschtmann, D., Stoyanov, J. V., Gedet, P. & Ferguson, S. J. Vertebral endplate trauma induces disc cell apoptosis and promotes organ degeneration in vitro. Eur. Spine J. 17, 289–299 (2008).
Vo, N. V. et al. Molecular mechanisms of biological aging in intervertebral discs. J. Orthopaed. Res. 34, 1289–1306 (2016).
Ospelt, C. Synovial fibroblasts in 2017. RMD Open 3, e000471 (2017).
Ryu, J. H. et al. Hypoxia-inducible factor-2α regulates Fas-mediated chondrocyte apoptosis during osteoarthritic cartilage destruction. Cell Death Differ. 19, 440–450 (2012).
Nakawaki, M. et al. Changes in nerve growth factor expression and macrophage phenotype following intervertebral disc injury in mice. J. Orthopaed. Res. 37, 1798–1804 (2019).
Wang, D., Chai, X. Q., Hu, S. S. & Pan, F. Joint synovial macrophages as a potential target for intra-articular treatment of osteoarthritis-related pain. Osteoarthr. Cartil. https://doi.org/10.1016/j.joca.2021.11.014 (2021).
Hsueh, M. F., Zhang, X., Wellman, S. S., Bolognesi, M. P. & Kraus, V. B. Synergistic roles of macrophages and neutrophils in osteoarthritis progression. Arthritis Rheumatol. 73, 89–99 (2021).
Kaneva, M. K. Neutrophil elastase and its inhibitors-overlooked players in osteoarthritis. FEBS J. 289, 113–116 (2022).
Wang, G. et al. Neutrophil elastase induces chondrocyte apoptosis and facilitates the occurrence of osteoarthritis via caspase signaling pathway. Front. Pharmacol. 12, 666162 (2021).
Chatham, W. W. et al. Degradation of human articular cartilage by neutrophils in synovial fluid. Arthritis Rheum. 36, 51–58 (1993).
Muley, M. M., Krustev, E., Reid, A. R. & McDougall, J. J. Prophylactic inhibition of neutrophil elastase prevents the development of chronic neuropathic pain in osteoarthritic mice. J. Neuroinflammation 14, 168 (2017).
Yuan, Y. et al. Association between chronic inflammation and latent infection of Propionibacterium acnes in non-pyogenic degenerated intervertebral discs: a pilot study. Eur. Spine J. 27, 2506–2517 (2018).
Rajasekaran, S. et al. Novel biomarkers of health and degeneration in human intervertebral discs: in-depth proteomic analysis of collagen framework of fetal, healthy, scoliotic, degenerate, and herniated discs. Asian Spine J. https://doi.org/10.31616/asj.2021.0535 (2022).
Gorth, D. J., Shapiro, I. M. & Risbud, M. V. Transgenic mice overexpressing human TNF-α experience early onset spontaneous intervertebral disc herniation in the absence of overt degeneration. Cell Death Dis. 10, 7 (2018).
Ma, X., Su, J., Wang, B. & Jin, X. Identification of characteristic genes in whole blood of intervertebral disc degeneration patients by weighted gene coexpression network analysis (WGCNA). Comput. Math. Meth. Med. 2022, 6609901 (2022).
Liu, W. et al. Single-cell profiles of age-related osteoarthritis uncover underlying heterogeneity associated with disease progression. Front. Mol. Biosci. 8, 748360 (2021).
Zhu, W. et al. Alterations in peripheral T cell and B cell subsets in patients with osteoarthritis. Clin. Rheumatol. 39, 523–532 (2020).
Collins Kelsey, H. et al. Adipose tissue is a critical regulator of osteoarthritis. Proc. Natl Acad. Sci. USA 118, e2021096118 (2021).
Ching, K., Houard, X., Berenbaum, F. & Wen, C. Hypertension meets osteoarthritis - revisiting the vascular aetiology hypothesis. Nat. Rev. Rheumatol. 17, 533–549 (2021).
Hu, Y., Chen, X., Wang, S., Jing, Y. & Su, J. Subchondral bone microenvironment in osteoarthritis and pain. Bone Res. 9, 20 (2021).
Kim, J. S. et al. Characterization of degenerative human facet joints and facet joint capsular tissues. Osteoarthr. Cartil. 23, 2242–2251 (2015).
Zhang, S. et al. The role of structure and function changes of sensory nervous system in intervertebral disc-related low back pain. Osteoarthr. Cartil. 29, 17–27 (2021).
Zhang, Y. et al. Single-cell RNA-seq analysis identifies unique chondrocyte subsets and reveals involvement of ferroptosis in human intervertebral disc degeneration. Osteoarthr. Cartil. 29, 1324–1334 (2021).
Lotz, J. C., Fields, A. J. & Liebenberg, E. C. The role of the vertebral end plate in low back pain. Glob. Spine J. 3, 153–164 (2013).
Miyagi, M. et al. ISSLS Prize winner: increased innervation and sensory nervous system plasticity in a mouse model of low back pain due to intervertebral disc degeneration. Spine 39, 1345–1354 (2014).
Groh, A. M. R., Fournier, D. E., Battié, M. C. & Séguin, C. A. Innervation of the human intervertebral disc: a scoping review. Pain Med. 22, 1281–1304 (2021).
Miller, R. J., Malfait, A. M. & Miller, R. E. The innate immune response as a mediator of osteoarthritis pain. Osteoarthr. Cartil. 28, 562–571 (2020).
Luo, L. et al. Injectable cartilage matrix hydrogel loaded with cartilage endplate stem cells engineered to release exosomes for non-invasive treatment of intervertebral disc degeneration. Bioact. Mater. 15, 29–43 (2022).
Yang, L., Li, Z. & Ouyang, Y. Taurine attenuates ER stress-associated apoptosis and catabolism in nucleus pulposus cells. Mol. Med. Rep. https://doi.org/10.3892/mmr.2022.12688 (2022).
Xu, D. et al. MMP-1 overexpression induced by IL-1β: possible mechanism for inflammation in degenerative lumbar facet joint. J. Orthopaed. Sci. 18, 1012–1019 (2013).
Shang, P., Liu, Y. & Jia, J. Paeonol inhibits inflammatory response and protects chondrocytes by upregulating sirtuin 1. Can. J. Physiol. Pharmacol. 100, 283–290 (2022).
Zhang, H., Zheng, W., Li, D. & Zheng, J. MiR-379-5p Promotes chondrocyte proliferation via inhibition of PI3K/Akt pathway by targeting YBX1 in osteoarthritis. Cartilage 13, 19476035221074024 (2022).
Xu, K., Gao, Y., Yang, L., Liu, Y. & Wang, C. Magnolin exhibits anti-inflammatory effects on chondrocytes via the NF-κB pathway for attenuating anterior cruciate ligament transection-induced osteoarthritis. Connect. Tissue Res. 62, 475–484 (2021).
Wang, A. et al. Shikonin, a promising therapeutic drug for osteoarthritis that acts via autophagy activation. Int. Immunopharmacol. 106, 108563 (2022).
Liu, C. & Chen, Y. Ketorolac tromethamine alleviates IL-1β-induced chondrocyte injury by inhibiting COX-2 expression. Exp. Ther. Med. 23, 337 (2022).
Kalichman, L. & Hunter, D. J. The genetics of intervertebral disc degeneration. Associated genes. Joint Bone Spine 75, 388–396 (2008).
Zhu, M. et al. lncRNA LINC00284 promotes nucleus pulposus cell proliferation and ECM synthesis via regulation of the miR-205-3p/Wnt/β-catenin axis. Mol. Med. Rep. https://doi.org/10.3892/mmr.2022.12695 (2022).
Zheng, H. L. et al. Increased expression of prolyl endopeptidase induced by oxidative stress in nucleus pulposus cells aggravates intervertebral disc degeneration. Oxid. Med. Cell. Longev. 2022, 9731800 (2022).
Song, J. et al. Exosome-transported circRNA_0000253 competitively adsorbs microRNA-141-5p and increases IDD. Mol. Ther. Nucleic Acids 21, 1087–1099 (2020).
Jing, W. & Liu, W. HOXC13-AS Induced extracellular matrix loss via targeting miR-497-5p/ADAMTS5 in intervertebral disc. Front. Mol. Biosci. 8, 643997 (2021).
Du, X. F. et al. Role of the miR-133a-5p/FBXO6 axis in the regulation of intervertebral disc degeneration. J. Orthop. Transl. 29, 123–133 (2021).
Zhang, T. W. et al. Decorin inhibits nucleus pulposus apoptosis by matrix-induced autophagy via the mTOR pathway. J. Orthopaed. Res. 39, 1777–1788 (2021).
Nabavizadeh, S. S. et al. Attenuation of osteoarthritis progression through intra-articular injection of a combination of synovial membrane-derived MSCs (SMMSCs), platelet-rich plasma (PRP) and conditioned medium (secretome). J. Orthopaed. Surg. Res. 17, 102 (2022).
Wang, Z., Rao, Z., Wang, X., Jiang, C. & Yang, Y. circPhc3 sponging microRNA-93-3p is involved in the regulation of chondrocyte function by mechanical instability in osteoarthritis. Int. J. Mol. Med. https://doi.org/10.3892/ijmm.2021.5061 (2022).
Feng, M. et al. Circ_0020093 ameliorates IL-1β-induced apoptosis and extracellular matrix degradation of human chondrocytes by upregulating SPRY1 via targeting miR-23b. Mol. Cell. Biochem. 476, 3623–3633 (2021).
Li, M., Peng, Z., Wang, X. & Wang, Y. Monoamine oxidase A attenuates chondrocyte loss and extracellular matrix degradation in osteoarthritis by inducing autophagy. Int. Immunopharmacol. 109, 108772 (2022).
Bai, X. et al. Cyanidin attenuates the apoptosis of rat nucleus pulposus cells and the degeneration of intervertebral disc via the JAK2/STAT3 signal pathway in vitro and in vivo. Pharm. Biol. 60, 427–436 (2022).
Chen, D. & Jiang, X. Exosomes-derived miR-125-5p from cartilage endplate stem cells regulates autophagy and ECM metabolism in nucleus pulposus by targeting SUV38H1. Exp. Cell Res. 414, 113066 (2022).
Ma, H. et al. MFG-E8 alleviates intervertebral disc degeneration by suppressing pyroptosis and extracellular matrix degradation in nucleus pulposus cells via Nrf2/TXNIP/NLRP3 axis. Cell Death Discov. 8, 209 (2022).
Liu, J., Yu, P., Dai, F., Jiang, H. & Ma, Z. Tetrandrine reduces oxidative stress, apoptosis, and extracellular matrix degradation and improves intervertebral disc degeneration by inducing autophagy. Bioengineered 13, 3944–3957 (2022).
Yang, S. & Liao, W. Hydroxysafflor yellow A attenuates oxidative stress injury-induced apoptosis in the nucleus pulposus cell line and regulates extracellular matrix balance via CA XII. Exp. Ther. Med. 23, 182 (2022).
Shao, M., Lv, D., Zhou, K., Sun, H. & Wang, Z. Senkyunolide A inhibits the progression of osteoarthritis by inhibiting the NLRP3 signalling pathway. Pharm. Biol. 60, 535–542 (2022).
Liu, Y., Li, Q., Gao, Z., Lei, F. & Gao, X. Circ-SPG11 knockdown hampers IL-1β-induced osteoarthritis progression via targeting miR-337-3p/ADAMTS5. J. Orthopaed. Surg. Res. 16, 392 (2021).
Lin, Z. et al. Echinacoside upregulates Sirt1 to suppress endoplasmic reticulum stress and inhibit extracellular matrix degradation in vitro and ameliorates osteoarthritis in vivo. Oxid. Med. Cell. Longev. 2021, 3137066 (2021).
Lv, S. et al. Quercetin mediates TSC2-RHEB-mTOR pathway to regulate chondrocytes autophagy in knee osteoarthritis. Gene 820, 146209 (2022).
Endisha, H. et al. MicroRNA-34a-5p promotes joint destruction during osteoarthritis. Arthritis Rheumatol. 73, 426–439 (2021).
Zhang, M., Mou, L., Liu, S., Sun, F. & Gong, M. Circ_0001103 alleviates IL-1β-induced chondrocyte cell injuries by upregulating SIRT1 via targeting miR-375. Clin. Immunol. 227, 108718 (2021).
Chen, S. et al. Grem1 accelerates nucleus pulposus cell apoptosis and intervertebral disc degeneration by inhibiting TGF-β-mediated Smad2/3 phosphorylation. Exp. Mol. Med. https://doi.org/10.1038/s12276-022-00753-9 (2022).
Zhang, Y., Liu, C., Li, Y. & Xu, H. Mechanism of the mitogen-activated protein kinases/mammalian target of rapamycin pathway in the process of cartilage endplate stem cell degeneration induced by tension load. Glob. Spine J. https://doi.org/10.1177/21925682221085226 (2022).
Guo, Y. et al. Is there any relationship between plasma IL-6 and TNF-α levels and lumbar disc degeneration? A retrospective single-center study. Dis. Markers 2022, 6842130 (2022).
Li, X. et al. MicroRNA-10a-3p improves cartilage degeneration by regulating CH25H-CYP7B1-RORα mediated cholesterol metabolism in knee osteoarthritis rats. Front. Pharmacol. 12, 690181 (2021).
Sugimoto, K. et al. Angiopoietin-like protein 2 induces synovial inflammation in the facet joint leading to degenerative changes via interleukin-6 secretion. Asian Spine J. 13, 368–376 (2019).
Dong, X. Y., Yin, J. X., Zhang, H. & Liao, Y. High glucose stimulating ECM remodeling and an inflammatory phenotype in the IPFP via upregulation of MFAP5 expression. Biochem. Biophys. Res. Commun. 601, 93–100 (2022).
Mei, X., Tong, J., Zhu, W. & Zhu, Y. lncRNA-NR024118 overexpression reverses LPS-induced inflammatory injury and apoptosis via NF-κB/Nrf2 signaling in ATDC5 chondrocytes. Mol. Med. Rep. 20, 3867–3873 (2019).
Lan, T., Shen, Z., Hu, Z. & Yan, B. Vitamin D/VDR in the pathogenesis of intervertebral disc degeneration: Does autophagy play a role. Biomed. Pharmacother. 148, 112739 (2022).
Li, H.-M., Liu, Y., Zhang, R.-J., Ding, J.-Y. & Shen, C.-L. Vitamin D receptor gene polymorphisms and osteoarthritis: a meta-analysis. Rheumatology 60, 538–548 (2020).
Yurube, T. et al. Involvement of autophagy in rat tail static compression-induced intervertebral disc degeneration and notochordal cell disappearance. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22115648 (2021).
Gong, C. Y. & Zhang, H. H. Autophagy as a potential therapeutic target in intervertebral disc degeneration. Life Sci. 273, 119266 (2021).
Sun, K. et al. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthr. Cartil. 28, 400–409 (2020).
Li, Z. et al. CsA attenuates compression-induced nucleus pulposus mesenchymal stem cells apoptosis via alleviating mitochondrial dysfunction and oxidative stress. Life Sci. 205, 26–37 (2018).
Patel, S., Mishra, N. P., Chouhan, D. K., Nahar, U. & Dhillon, M. S. Chondroprotective effects of multiple PRP injections in osteoarthritis by apoptosis regulation and increased aggrecan synthesis- Immunohistochemistry based Guinea pig study. J. Clin. Orthop. Trauma 25, 101762 (2022).
Zhang, L., Sui, C., Zhang, Y., Wang, G. & Yin, Z. Knockdown of hsa_circ_0134111 alleviates the symptom of osteoarthritis via sponging microRNA-224-5p. Cell Cycle 20, 1052–1066 (2021).
Pan, D. et al. RIP2 knockdown inhibits cartilage degradation and oxidative stress in IL-1β-treated chondrocytes via regulating TRAF3 and inhibiting p38 MAPK pathway. Clin. Immunol. 232, 108868 (2021).
The work of R.R. and N.F. is supported by a J. Bernard Gosevitz Chair. The work of M.K. is supported in part by a Tier 1 Canada Research Chair in the mechanisms of joint degeneration and a Tony and Shari Fell Platinum Chair in Arthritis Research. The work of A.V.P. is supported by an award from Arthritis Society Canada (STAR-20-0000000012).
R.R. and M.K. declare a US patent No US10888577B2: PCT international patent WO2017143430A1, entitled “MiRNA biomarkers for cartilage degeneration”. M.K. declares that he filed a US Provisional Patent Application no. 63/033,463, entitled “Circulating MicroRNAs in Early Knee Osteoarthritis and Uses Thereof”. The other authors declare no competing interests.
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A class of cytokines produced by the adipose tissue.
Programmed death of a cell.
A process by which cells break down and recycle intracellular components.
An embryonic rod-like structure that functions as a precursor to the spine.
Bony projections resulting from increased bone remodelling activity.
- Pelvic incidence
A fixed, innate angle between the sacrum and pelvis that typically dictates the sagittal curvature of the mobile spine.
The embryonic tissue that gives rise to the skeleton.
The loss of proliferative potential in a cell.
An embryonic compartment that serves as a precursor that gives rise to the axial tendons.
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Fine, N., Lively, S., Séguin, C.A. et al. Intervertebral disc degeneration and osteoarthritis: a common molecular disease spectrum. Nat Rev Rheumatol 19, 136–152 (2023). https://doi.org/10.1038/s41584-022-00888-z