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Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis

  • 1.

    Vincent, T. L. & Wann, A. K. Mechanoadaptation: articular cartilage through thick and thin. J. Physiol. 597, 1271–1281 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • 2.

    Chang, S. H. et al. Excessive mechanical loading promotes osteoarthritis through the gremlin-1–NF-κB pathway. Nat. Commun. 10, 1442 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 3.

    Goldring, S. R. & Goldring, M. B. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage–bone crosstalk. Nat. Rev. Rheumatol. 12, 632–644 (2016).

    PubMed 

    Google Scholar 

  • 4.

    Pap, T. & Korb-Pap, A. Cartilage damage in osteoarthritis and rheumatoid arthritis — two unequal siblings. Nat. Rev. Rheumatol. 11, 606–615 (2015).

    PubMed 

    Google Scholar 

  • 5.

    Burr, D. B. & Gallant, M. A. Bone remodelling in osteoarthritis. Nat. Rev. Rheumatol. 8, 665–673 (2012).

    CAS 
    PubMed 

    Google Scholar 

  • 6.

    Collins, K. H. et al. Adipose tissue is a critical regulator of osteoarthritis. Proc. Natl Acad. Sci. USA 118, e2021096118 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • 7.

    Watt, F. E. Posttraumatic osteoarthritis: what have we learned to advance osteoarthritis? Curr. Opin. Rheumatol. 33, 74–83 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • 8.

    Greene, M. A. & Loeser, R. F. Aging-related inflammation in osteoarthritis. Osteoarthritis Cartilage 23, 1966–1971 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 9.

    McNulty, M. A. et al. Histopathology of naturally occurring and surgically induced osteoarthritis in mice. Osteoarthritis Cartilage 20, 949–956 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 10.

    Lotz, M. & Loeser, R. F. Effects of aging on articular cartilage homeostasis. Bone 51, 241–248 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 11.

    Loeser, R. F. et al. Microarray analysis reveals age‐related differences in gene expression during the development of osteoarthritis in mice. Arthritis Rheum. 64, 705–717 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 12.

    Thomas, A. C., Hubbard-Turner, T., Wikstrom, E. A. & Palmieri-Smith, R. M. Epidemiology of posttraumatic osteoarthritis. J. Athlet. Train. 52, 491–496 (2017).

    Google Scholar 

  • 13.

    Glasson, S. S. et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644–648 (2005).

    CAS 
    PubMed 

    Google Scholar 

  • 14.

    Burleigh, A. et al. Joint immobilization prevents murine osteoarthritis and reveals the highly mechanosensitive nature of protease expression in vivo. Arthritis Rheum. 64, 2278–2288 (2012).

    CAS 
    PubMed 

    Google Scholar 

  • 15.

    Ismail, H. M. et al. Interleukin‐1 acts via the JNK‐2 signaling pathway to induce aggrecan degradation by human chondrocytes. Arthritis Rheumatol. 67, 1826–1836 (2015).

    CAS 
    PubMed 

    Google Scholar 

  • 16.

    Zhang, M. et al. Induced superficial chondrocyte death reduces catabolic cartilage damage in murine posttraumatic osteoarthritis. J. Clin. Invest. 126, 2893–2902 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 17.

    Gilbert, S. J. & Blain, E. J. in Mechanobiology in Health and Disease (ed. Verbruggen, S. W.) 99–126 (Elsevier, 2018).

  • 18.

    Guilak, F., Nims, R. J., Dicks, A., Wu, C.-L. & Meulenbelt, I. Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol. 71–72, 40–50 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 19.

    Vincent, T. L. Targeting mechanotransduction pathways in osteoarthritis: a focus on the pericellular matrix. Curr. Opin. Pharmacol. 13, 449–454 (2013).

    CAS 
    PubMed 

    Google Scholar 

  • 20.

    Agarwal, P. et al. A dysfunctional TRPV4–GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity. Nat. Biomed. Eng. 5, 1472–1484 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • 21.

    Nims, R. J. et al. A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues. Sci. Adv. 7, eabd9858 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 22.

    Deng, Y. et al. Reciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation. Nat. Commun. 9, 4564 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 23.

    Eckstein, F. et al. Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of location in the femorotibial joint: post-hoc analysis of a randomised, placebo-controlled phase II clinical trial. Ann. Rheum. Dis. 79, 525–528 (2020).

    PubMed 

    Google Scholar 

  • 24.

    Peredo, A. P. et al. Mechano-activated biomolecule release in regenerating load-bearing tissue microenvironments. Biomaterials 265, 120255 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • 25.

    Nims, R. J., Pferdehirt, L. & Guilak, F. Mechanogenetics: harnessing mechanobiology for cellular engineering. Curr. Opin. Biotechnol. 73, 374–379 (2022).

    CAS 

    Google Scholar 

  • 26.

    Poole, A. R. et al. Composition and structure of articular cartilage: a template for tissue repair. Clin. Orthop. Relat. Res. 391, S26–S33 (2001).

    Google Scholar 

  • 27.

    Mow, V. C., Ratcliffe, A. & Poole, A. R. Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. Biomaterials 13, 67–97 (1992).

    CAS 
    PubMed 

    Google Scholar 

  • 28.

    Schätti, O. R., Marková, M., Torzilli, P. A. & Gallo, L. M. Mechanical loading of cartilage explants with compression and sliding motion modulates gene expression of lubricin and catabolic enzymes. Cartilage 6, 185–193 (2015).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 29.

    Melrose, J., Hayes, A. J., Whitelock, J. M. & Little, C. B. Perlecan, the “jack of all trades” proteoglycan of cartilaginous weight‐bearing connective tissues. Bioessays 30, 457–469 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • 30.

    Poole, C. A. Articular cartilage chondrons: form, function and failure. J. Anat. 191, 1–13 (1997).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 31.

    Schinagl, R. M., Gurskis, D., Chen, A. C. & Sah, R. L. Depth‐dependent confined compression modulus of full‐thickness bovine articular cartilage. J. Ortho Res. 15, 499–506 (1997).

    CAS 

    Google Scholar 

  • 32.

    Xia, Y., Moody, J. B., Alhadlaq, H. & Hu, J. Imaging the physical and morphological properties of a multi‐zone young articular cartilage at microscopic resolution. J. Mag. Reson. Imaging 17, 365–374 (2003).

    Google Scholar 

  • 33.

    Ratcliffe, A., Fryer, P. R. & Hardingham, T. E. The distribution of aggregating proteoglycans in articular cartilage: comparison of quantitative immunoelectron microscopy with radioimmunoassay and biochemical analysis. J. Histochem. Cytochem. 32, 193–201 (1984).

    CAS 
    PubMed 

    Google Scholar 

  • 34.

    Maroudas, A., Muir, H. & Wingham, J. The correlation of fixed negative charge with glycosaminoglycan content of human articular cartilage. Biochim. Biophys. Acta 177, 492–500 (1969).

    CAS 
    PubMed 

    Google Scholar 

  • 35.

    Wilusz, R. E., Zauscher, S. & Guilak, F. Micromechanical mapping of early osteoarthritic changes in the pericellular matrix of human articular cartilage. Osteoarthritis Cartilage 21, 1895–1903 (2013).

    CAS 
    PubMed 

    Google Scholar 

  • 36.

    Chery, D. R. et al. Early changes in cartilage pericellular matrix micromechanobiology portend the onset of post-traumatic osteoarthritis. Acta Biomater. 111, 267–278 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 37.

    Simon, W. H. Scale effects in animal joints. I. Articular cartilage thickness and compressive stress. Arthritis Rheum. 13, 244–255 (1970).

    CAS 
    PubMed 

    Google Scholar 

  • 38.

    Loeser, R. F. Integrins and cell signaling in chondrocytes. Biorheology 39, 119–124 (2002).

    CAS 
    PubMed 

    Google Scholar 

  • 39.

    Millward-Sadler, S. J. & Salter, D. M. Integrin-dependent signal cascades in chondrocyte mechanotransduction. Ann. Biomed. Eng. 32, 435–446 (2004).

    CAS 
    PubMed 

    Google Scholar 

  • 40.

    Ross, T. D. et al. Integrins in mechanotransduction. Curr. Opin. Cell Biol. 25, 613–618 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 41.

    Blain, E. J. Involvement of the cytoskeletal elements in articular cartilage homeostasis and pathology. Int. J. Exp. Pathol. 90, 1–15 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 42.

    Barrett-Jolley, R., Lewis, R., Fallman, R. & Mobasheri, A. The emerging chondrocyte channelome. Front. Physiol. 1, 135 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 43.

    Matta, C., Zákány, R. & Mobasheri, A. Voltage-dependent calcium channels in chondrocytes: roles in health and disease. Curr. Rheumatol. Rep. 17, 43 (2015).

    PubMed 

    Google Scholar 

  • 44.

    Mobasheri, A. et al. The chondrocyte channelome: a narrative review. Jt. Bone Spine 86, 29–35 (2019).

    CAS 

    Google Scholar 

  • 45.

    Ruhlen, R. & Marberry, K. The chondrocyte primary cilium. Osteoarthritis Cartilage 22, 1071–1076 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • 46.

    Tao, F., Jiang, T., Tao, H., Cao, H. & Xiang, W. Primary cilia: versatile regulator in cartilage development. Cell Prolif. 53, e12765 (2020).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 47.

    Guilak, F. et al. The pericellular matrix as a transducer of biomechanical and biochemical signals in articular cartilage. Ann. N. Y. Acad. Sci. 1068, 498–512 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • 48.

    Youn, I., Choi, J., Cao, L., Setton, L. & Guilak, F. Zonal variations in the three-dimensional morphology of the chondron measured in situ using confocal microscopy. Osteoarthritis Cartilage 14, 889–897 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • 49.

    Martin, J., Miller, B., Scherb, M., Lembke, L. & Buckwalter, J. Co-localization of insulin-like growth factor binding protein 3 and fibronectin in human articular cartilage. Osteoarthritis Cartilage 10, 556–563 (2002).

    CAS 
    PubMed 

    Google Scholar 

  • 50.

    Vincent, T., Hermansson, M., Bolton, M., Wait, R. & Saklatvala, J. Basic FGF mediates an immediate response of articular cartilage to mechanical injury. Proc. Natl Acad. Sci. USA 99, 8259–8264 (2002).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 51.

    Vincent, T. L., Hermansson, M. A., Hansen, U. N., Amis, A. A. & Saklatvala, J. Basic fibroblast growth factor mediates transduction of mechanical signals when articular cartilage is loaded. Arthritis Rheum. 50, 526–533 (2004).

    CAS 
    PubMed 

    Google Scholar 

  • 52.

    Vincent, T. L., McLean, C. J., Full, L. E., Peston, D. & Saklatvala, J. FGF-2 is bound to perlecan in the pericellular matrix of articular cartilage, where it acts as a chondrocyte mechanotransducer. Osteoarthritis Cartilage 15, 752–763 (2007).

    CAS 
    PubMed 

    Google Scholar 

  • 53.

    Vincent, T. L. Fibroblast growth factor 2: good or bad guy in the joint? Arthritis Res. Ther. 13, 127 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 54.

    Xie, Y., Zinkle, A., Chen, L. & Mohammadi, M. Fibroblast growth factor signalling in osteoarthritis and cartilage repair. Nat. Rev. Rheumatol. 16, 547–564 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • 55.

    Makarenkova, H. P. et al. Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis. Sci. Signal. 2, ra55 (2009).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 56.

    Eckstein, F., Wirth, W., Guermazi, A., Maschek, S. & Aydemir, A. Brief report: intraarticular sprifermin not only increases cartilage thickness, but also reduces cartilage loss: location‐independent post hoc analysis using magnetic resonance imaging. Arthritis Rheumatol. 67, 2916–2922 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 57.

    Lohmander, L. S. et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double‐blind, placebo‐controlled trial. Arthritis Rheumatol. 66, 1820–1831 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • 58.

    Hochberg, M. C. et al. Effect of intra-articular sprifermin vs placebo on femorotibial joint cartilage thickness in patients with osteoarthritis: the FORWARD randomized clinical trial. JAMA 322, 1360–1370 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 59.

    Zhen, G. et al. Mechanical stress determines the configuration of TGFβ activation in articular cartilage. Nat. Commun. 12, 1706 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 60.

    Kechagia, J. Z., Ivaska, J. & Roca-Cusachs, P. Integrins as biomechanical sensors of the microenvironment. Nat. Rev. Mol. Cell Biol. 20, 457–473 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • 61.

    Seetharaman, S. & Etienne‐Manneville, S. Integrin diversity brings specificity in mechanotransduction. Biol. Cell 110, 49–64 (2018).

    CAS 
    PubMed 

    Google Scholar 

  • 62.

    Cantini, M., Donnelly, H., Dalby, M. J. & Salmeron‐Sanchez, M. The plot thickens: the emerging role of matrix viscosity in cell mechanotransduction. Adv. Healthc. Mater. 9, 1901259 (2020).

    CAS 

    Google Scholar 

  • 63.

    Parsons, J. T., Horwitz, A. R. & Schwartz, M. A. Cell adhesion: integrating cytoskeletal dynamics and cellular tension. Nat. Rev. Mol. Cell Biol. 11, 633–643 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 64.

    Puklin-Faucher, E. & Sheetz, M. P. The mechanical integrin cycle. J. Cell Sci. 122, 179–186 (2009).

    CAS 
    PubMed 

    Google Scholar 

  • 65.

    Elosegui-Artola, A. et al. Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity. Nat. Cell Biol. 18, 540–548 (2016).

    CAS 
    PubMed 

    Google Scholar 

  • 66.

    Elosegui-Artola, A. et al. Rigidity sensing and adaptation through regulation of integrin types. Nat. Mater. 13, 631–637 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 67.

    Franz, F., Daday, C. & Gräter, F. Advances in molecular simulations of protein mechanical properties and function. Curr. Opin. Struct. Biol. 61, 132–138 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • 68.

    Gouttenoire, J. et al. BMP-2 and TGF-β1 differentially control expression of type II procollagen and α10 and α11 integrins in mouse chondrocytes. Eur. J. Cell Biol. 89, 307–314 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 69.

    Salter, D., Hughes, D., Simpson, R. & Gardner, D. Integrin expression by human articular chondrocytes. Rheumatology 31, 231–234 (1992).

    CAS 

    Google Scholar 

  • 70.

    Zhang, W.-M. et al. Analysis of the human integrin α11 gene (ITGA11) and its promoter. Matrix Biol. 21, 513–523 (2002).

    CAS 
    PubMed 

    Google Scholar 

  • 71.

    Loeser, R. F. Integrins and chondrocyte–matrix interactions in articular cartilage. Matrix Biol. 39, 11–16 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 72.

    Orazizadeh, M. et al. CD47 associates with alpha 5 integrin and regulates responses of human articular chondrocytes to mechanical stimulation in an in vitro model. Arthritis Res. Ther. 10, R4 (2008).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 73.

    Ostergaard, K. et al. Expression of α and β subunits of the integrin superfamily in articular cartilage from macroscopically normal and osteoarthritic human femoral heads. Ann. Rheum. Dis. 57, 303–308 (1998).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 74.

    Lucchinetti, E., Bhargava, M. M. & Torzilli, P. A. The effect of mechanical load on integrin subunits α5 and β1 in chondrocytes from mature and immature cartilage explants. Cell Tissue Res. 315, 385–391 (2004).

    CAS 
    PubMed 

    Google Scholar 

  • 75.

    Millward-Sadler, S. et al. Integrin-regulated secretion of interleukin 4: a novel pathway of mechanotransduction in human articular chondrocytes. J. Cell Biol. 145, 183–189 (1999).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 76.

    Millward‐Sadler, S., Wright, M., Davies, L., Nuki, G. & Salter, D. Mechanotransduction via integrins and interleukin‐4 results in altered aggrecan and matrix metalloproteinase 3 gene expression in normal, but not osteoarthritic, human articular chondrocytes. Arthritis Rheum. 43, 2091–2099 (2000).

    PubMed 

    Google Scholar 

  • 77.

    Steward, A. et al. Cell–matrix interactions regulate mesenchymal stem cell response to hydrostatic pressure. Acta Biomater. 8, 2153–2159 (2012).

    CAS 
    PubMed 

    Google Scholar 

  • 78.

    Jablonski, C. L., Ferguson, S., Pozzi, A. & Clark, A. L. Integrin α1β1 participates in chondrocyte transduction of osmotic stress. Biochem. Biophys. Res. Commun. 445, 184–190 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 79.

    Wright, M. et al. Hyperpolarisation of cultured human chondrocytes following cyclical pressure‐induced strain: evidence of a role for α5β1 integrin as a chondrocyte mechanoreceptor. J. Ortho Res. 15, 742–747 (1997).

    CAS 

    Google Scholar 

  • 80.

    Camper, L., Hellman, U. & Lundgren-Åkerlund, E. Isolation, cloning, and sequence analysis of the integrin subunit α10, a β1-associated collagen binding integrin expressed on chondrocytes. J. Biol. Chem. 273, 20383–20389 (1998).

    CAS 
    PubMed 

    Google Scholar 

  • 81.

    Bengtsson, T., Camper, L., Schneller, M. & Lundgren-Åkerlund, E. Characterization of the mouse integrin subunit α10 gene and comparison with its human homologue: genomic structure, chromosomal localization and identification of splice variants. Matrix Biol. 20, 565–576 (2001).

    CAS 
    PubMed 

    Google Scholar 

  • 82.

    Lehnert, K. et al. Cloning, sequence analysis, and chromosomal localization of the novel human integrin α11 subunit (ITGA11). Genomics 60, 179–187 (1999).

    CAS 
    PubMed 

    Google Scholar 

  • 83.

    Varas, L. et al. α10 integrin expression is up-regulated on fibroblast growth factor-2-treated mesenchymal stem cells with improved chondrogenic differentiation potential. Stem Cell Dev. 16, 965–978 (2007).

    CAS 

    Google Scholar 

  • 84.

    Delco, M. L. et al. Integrin α10β1-selected mesenchymal stem cells mitigate the progression of osteoarthritis in an equine talar impact model. Am. J. Sports Med. 48, 612–623 (2020).

    PubMed 

    Google Scholar 

  • 85.

    Hirose, N. et al. Protective effects of cilengitide on inflammation in chondrocytes under excessive mechanical stress. Cell Biol. Int. 44, 966–974 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • 86.

    Chao, P. H., West, A. C. & Hung, C. T. Chondrocyte intracellular calcium, cytoskeletal organization, and gene expression responses to dynamic osmotic loading. Am. J. Physiol. Cell Physiol. 291, 718–725 (2006).

    Google Scholar 

  • 87.

    Erickson, G. R., Northrup, D. L. & Guilak, F. Hypo-osmotic stress induces calcium-dependent actin reorganization in articular chondrocytes. Osteoarthritis Cartilage 11, 187–197 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • 88.

    Grodzinsky, A. J., Levenston, M. E., Jin, M. & Frank, E. H. Cartilage tissue remodeling in response to mechanical forces. Annu. Rev. Biomed. Eng. 2, 691–713 (2000).

    CAS 
    PubMed 

    Google Scholar 

  • 89.

    Guilak, F. Compression-induced changes in the shape and volume of the chondrocyte nucleus. J. Biomech. 28, 1529–1541 (1995).

    CAS 
    PubMed 

    Google Scholar 

  • 90.

    Blain, E. J., Mason, D. J. & Duance, V. C. The effect of thymosin β4 on articular cartilage chondrocyte matrix metalloproteinase expression. Biochem. Soc. Trans. 30, 879–882 (2002).

    CAS 
    PubMed 

    Google Scholar 

  • 91.

    Fioravanti, A., Nerucci, F., Annefeld, M., Collodel, G. & Marcolongo, R. Morphological and cytoskeletal aspects of cultivated normal and osteoarthritic human articular chondrocytes after cyclical pressure: a pilot study. Clin. Exp. Rheumatol. 21, 739–746 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • 92.

    Fioravanti, A., Benetti, D., Coppola, G. & Collodel, G. Effect of continuous high hydrostatic pressure on the morphology and cytoskeleton of normal and osteoarthritic human chondrocytes cultivated in alginate gels. Clin. Exp. Rheumatol. 23, 847–853 (2005).

    CAS 
    PubMed 

    Google Scholar 

  • 93.

    Isermann, P. & Lammerding, J. Nuclear mechanics and mechanotransduction in health and disease. Curr. Biol. 23, R1113–R1121 (2013).

    CAS 
    PubMed 

    Google Scholar 

  • 94.

    Khilan, A. A., Al-Maslamani, N. A. & Horn, H. F. Cell stretchers and the LINC complex in mechanotransduction. Arch. Biochem. Biophys. 702, 108829 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • 95.

    Lee, D. A. et al. Chondrocyte deformation within compressed agarose constructs at the cellular and sub-cellular levels. J. Biomech. 33, 81–95 (2000).

    CAS 
    PubMed 

    Google Scholar 

  • 96.

    Irianto, J. et al. Osmotic challenge drives rapid and reversible chromatin condensation in chondrocytes. Biophys. J. 104, 759–769 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 97.

    Hopewell, B. & Urban, J. P. Adaptation of articular chondrocytes to changes in osmolality. Biorheology 40, 73–77 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • 98.

    Hung, C. T. et al. Disparate aggrecan gene expression in chondrocytes subjected to hypotonic and hypertonic loading in 2D and 3D culture. Biorheology 40, 61–72 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • 99.

    Killaars, A. R., Walker, C. J. & Anseth, K. S. Nuclear mechanosensing controls MSC osteogenic potential through HDAC epigenetic remodeling. Proc. Natl Acad. Sci. USA 117, 21258 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 100.

    Elosegui-Artola, A. et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171, 1397–1410 (2017).

    CAS 
    PubMed 

    Google Scholar 

  • 101.

    Delco, M. L. & Bonassar, L. J. Targeting calcium-related mechanotransduction in early OA. Nat. Rev. Rheumatol. 17, 445–446 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • 102.

    O’Conor, C. J., Leddy, H. A., Benefield, H. C., Liedtke, W. B. & Guilak, F. TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proc. Natl Acad. Sci. USA 111, 1316–1321 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 103.

    Phan, M. N. et al. Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. Arthritis Rheum. 60, 3028–3037 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 104.

    Clark, A. L., Votta, B. J., Kumar, S., Liedtke, W. & Guilak, F. Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice. Arthritis Rheum. 62, 2973–2983 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 105.

    O’Conor, C. J. et al. Cartilage-specific knockout of the mechanosensory ion channel TRPV4 decreases age-related osteoarthritis. Sci. Rep. 6, 29053 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 106.

    Drexler, S. K., Wann, A. K. T. & Vincent, T. L. Are cellular mechanosensors potential therapeutic targets in osteoarthritis. Int. J. Clin. Rheumatol. 9, 155–167 (2014).

    CAS 

    Google Scholar 

  • 107.

    Lee, W., Guilak, F. & Liedtke, W. Role of Piezo channels in joint health and injury. Curr. Top. Membr. 79, 263–273 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 108.

    Sun, Y. et al. Mechanism of abnormal chondrocyte proliferation induced by Piezo1-siRNA exposed to mechanical stretch. BioMed. Res. Int. 2020, 8538463 (2020).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 109.

    Lee, W. et al. Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. Proc. Natl Acad. Sci. USA 111, E5114–E5122 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 110.

    Gnanasambandam, R. et al. GsMTx4: mechanism of inhibiting mechanosensitive ion channels. Biophys. J. 112, 31–45 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 111.

    Suchyna, T. M. Piezo channels and GsMTx4: two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology. Prog. Biophys. Mol. Biol. 130, 244–253 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 112.

    Xiao, W. F., Li, Y. S., Deng, A., Yang, Y. T. & He, M. Functional role of hedgehog pathway in osteoarthritis. Cell Biochem. Funct. 38, 122–129 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • 113.

    McGlashan, S. R., Cluett, E. C., Jensen, C. G. & Poole, C. A. Primary cilia in osteoarthritic chondrocytes: from chondrons to clusters. Dev. Dyn. 237, 2013–2020 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • 114.

    McGlashan, S. R., Jensen, C. G. & Poole, C. A. Localization of extracellular matrix receptors on the chondrocyte primary cilium. J. Histochem. Cytochem. 54, 1005–1014 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • 115.

    Chang, C. F., Ramaswamy, G. & Serra, R. Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis. Osteoarthritis Cartilage 20, 152–161 (2012).

    PubMed 

    Google Scholar 

  • 116.

    Irianto, J., Ramaswamy, G., Serra, R. & Knight, M. M. Depletion of chondrocyte primary cilia reduces the compressive modulus of articular cartilage. J. Biomech. 47, 579–582 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 117.

    Wann, A. K. T. et al. Primary cilia mediate mechanotransduction through control of ATP-induced Ca2+ signaling in compressed chondrocytes. FASEB J. 26, 1663–1671 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 118.

    Shao, Y. Y., Wang, L., Welter, J. F. & Ballock, R. T. Primary cilia modulate Ihh signal transduction in response to hydrostatic loading of growth plate chondrocytes. Bone 50, 79–84 (2012).

    CAS 
    PubMed 

    Google Scholar 

  • 119.

    Pingguan‐Murphy, B., El‐Azzeh, M., Bader, D. & Knight, M. Cyclic compression of chondrocytes modulates a purinergic calcium signalling pathway in a strain rate‐and frequency‐dependent manner. J. Cell Physiol. 209, 389–397 (2006).

    PubMed 

    Google Scholar 

  • 120.

    Zhang, J. et al. Connexin43 hemichannels mediate small molecule exchange between chondrocytes and matrix in biomechanically-stimulated temporomandibular joint cartilage. Osteoarthritis Cartilage 22, 822–830 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 121.

    Garcia, M. & Knight, M. M. Cyclic loading opens hemichannels to release ATP as part of a chondrocyte mechanotransduction pathway. J. Orthop. Res. 28, 510–515 (2010).

    CAS 
    PubMed 

    Google Scholar 

  • 122.

    Chowdhury, T. & Knight, M. Purinergic pathway suppresses the release of NO and stimulates proteoglycan synthesis in chondrocyte/agarose constructs subjected to dynamic compression. J. Cell Physiol. 209, 845–853 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • 123.

    Huang, C., Holfeld, J., Schaden, W., Orgill, D. & Ogawa, R. Mechanotherapy: revisiting physical therapy and recruiting mechanobiology for a new era in medicine. Trends Mol. Med. 19, 555–564 (2013).

    PubMed 

    Google Scholar 

  • 124.

    Thompson, W. R., Scott, A., Loghmani, M. T., Ward, S. R. & Warden, S. J. Understanding mechanobiology: physical therapists as a force in mechanotherapy and musculoskeletal regenerative rehabilitation. Phys. Ther. 96, 560–569 (2016).

    PubMed 

    Google Scholar 

  • 125.

    Dell’Accio, F., De Bari, C., Eltawil, N. M., Vanhummelen, P. & Pitzalis, C. Identification of the molecular response of articular cartilage to injury, by microarray screening: Wnt-16 expression and signaling after injury and in osteoarthritis. Arthritis Rheum. 58, 1410–1421 (2008).

    PubMed 

    Google Scholar 

  • 126.

    Loeser, R. F., Erickson, E. A. & Long, D. L. Mitogen-activated protein kinases as therapeutic targets in osteoarthritis. Curr. Opin. Rheumatol. 20, 581–586 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 127.

    Fanning, P. J. et al. Mechanical regulation of mitogen-activated protein kinase signaling in articular cartilage. J. Biol. Chem. 278, 50940–50948 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • 128.

    Forsyth, C. B., Pulai, J. & Loeser, R. F. Fibronectin fragments and blocking antibodies to α2β1 and α5β1 integrins stimulate mitogen‐activated protein kinase signaling and increase collagenase 3 (matrix metalloproteinase 13) production by human articular chondrocytes. Arthritis Rheum. 46, 2368–2376 (2002).

    CAS 
    PubMed 

    Google Scholar 

  • 129.

    Im, H.-J. et al. Inhibitory effects of insulin-like growth factor-1 and osteogenic protein-1 on fibronectin fragment- and interleukin-1β-stimulated matrix metalloproteinase-13 expression in human chondrocytes. J. Biol. Chem. 278, 25386–25394 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • 130.

    Loeser, R. F., Forsyth, C. B., Samarel, A. M. & Im, H.-J. Fibronectin fragment activation of proline-rich tyrosine kinase PYK2 mediates integrin signals regulating collagenase-3 expression by human chondrocytes through a protein kinase C-dependent pathway. J. Biol. Chem. 278, 24577–24585 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • 131.

    Pulai, J. I. et al. NF-κB mediates the stimulation of cytokine and chemokine expression by human articular chondrocytes in response to fibronectin fragments. J. Immunol. 174, 5781–5788 (2005).

    CAS 
    PubMed 

    Google Scholar 

  • 132.

    Del Carlo, M., Schwartz, D., Erickson, E. A. & Loeser, R. F. Endogenous production of reactive oxygen species is required for stimulation of human articular chondrocyte matrix metalloproteinase production by fibronectin fragments. Free. Radic. Biol. Med. 42, 1350–1358 (2007).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 133.

    Long, D. L., Willey, J. S. & Loeser, R. F. Rac1 is required for matrix metalloproteinase 13 production by chondrocytes in response to fibronectin fragments. Arthritis Rheum. 65, 1561–1568 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 134.

    Gemba, T., Valbracht, J., Alsalameh, S. & Lotz, M. Focal adhesion kinase and mitogen-activated protein kinases are involved in chondrocyte activation by the 29-kDa amino-terminal fibronectin fragment. J. Biol. Chem. 277, 907–911 (2002).

    CAS 
    PubMed 

    Google Scholar 

  • 135.

    Ding, L., Guo, D. & Homandberg, G. The cartilage chondrolytic mechanism of fibronectin fragments involves MAP kinases: comparison of three fragments and native fibronectin. Osteoarthritis Cartilage 16, 1253–1262 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • 136.

    Ding, L., Guo, D. & Homandberg, G. Fibronectin fragments mediate matrix metalloproteinase upregulation and cartilage damage through proline rich tyrosine kinase 2, c-src, NF-κB and protein kinase Cδ. Osteoarthritis Cartilage 17, 1385–1392 (2009).

    CAS 
    PubMed 

    Google Scholar 

  • 137.

    Fitzgerald, J. B. et al. Shear- and compression-induced chondrocyte transcription requires MAPK activation in cartilage explants. J. Biol. Chem. 283, 6735–6743 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • 138.

    Zhang, J., Shen, B. & Lin, A. Novel strategies for inhibition of the p38 MAPK pathway. Trends Pharmacol. Sci. 28, 286–295 (2007).

    PubMed 

    Google Scholar 

  • 139.

    González-Vázquez, A. et al. Accelerating bone healing in vivo by harnessing the age-altered activation of c-Jun N-terminal kinase 3. Biomaterials 268, 120540 (2021).

    PubMed 

    Google Scholar 

  • 140.

    Agarwal, S. et al. A central role for the nuclear factor-κB pathway in anti-inflammatory and proinflammatory actions of mechanical strain. FASEB J. 17, 899–901 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • 141.

    Yang, Y. et al. Mechanical stress protects against osteoarthritis via regulation of the AMPK/NF-κB signaling pathway. J. Cell Physiol. 234, 9156–9167 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • 142.

    Vincent, T. L. Mechanoflammation in osteoarthritis pathogenesis. Semin. Arthritis Rheum. 49, S36–S38 (2019).

    PubMed 

    Google Scholar 

  • 143.

    Ismail, H. M., Didangelos, A., Vincent, T. L. & Saklatvala, J. Rapid activation of transforming growth factor β-activated kinase 1 in chondrocytes by phosphorylation and K(63)-linked polyubiquitination upon injury to animal articular cartilage. Arthritis Rheumatol. 69, 565–575 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 144.

    Lee, W. et al. Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis. Proc. Natl Acad. Sci. USA 118, e2001611118 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 145.

    Nam, S. et al. Cell cycle progression in confining microenvironments is regulated by a growth-responsive TRPV4-PI3K/Akt-p27(Kip1) signaling axis. Sci. Adv. 5, eaaw6171 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 146.

    Lee, H. P., Gu, L., Mooney, D. J., Levenston, M. E. & Chaudhuri, O. Mechanical confinement regulates cartilage matrix formation by chondrocytes. Nat. Mater. 16, 1243–1251 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 147.

    Miller, J. R. The Wnts. Genome Biol. 3, reviews3001.1 (2001).

    Google Scholar 

  • 148.

    Blom, A. B. et al. Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt‐induced signaling protein 1. Arthritis Rheum. 60, 501–512 (2009).

    CAS 
    PubMed 

    Google Scholar 

  • 149.

    De Santis, M. et al. The role of Wnt pathway in the pathogenesis of OA and its potential therapeutic implications in the field of regenerative medicine. BioMed. Res. Int. 2018, 7402947 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 150.

    Dell’Accio, F. et al. Activation of WNT and BMP signaling in adult human articular cartilage following mechanical injury. Arthritis Res. Ther. 8, R139 (2006).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 151.

    Bougault, C. et al. Protective role of frizzled-related protein B on matrix metalloproteinase induction in mouse chondrocytes. Arthritis Res. Ther. 16, R137 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 152.

    Nalesso, G. et al. WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis. Ann. Rheum. Dis. 76, 218–226 (2017).

    CAS 
    PubMed 

    Google Scholar 

  • 153.

    Wang, Y., Fan, X., Xing, L. & Tian, F. Wnt signaling: a promising target for osteoarthritis therapy. Cell Commun. Signal. 17, 97 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 154.

    Lories, R. J. & Monteagudo, S. Review article: is Wnt signaling an attractive target for the treatment of osteoarthritis? Rheumatol. Ther. 7, 259–270 (2020).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 155.

    Monteagudo, S. & Lories, R. J. Cushioning the cartilage: a canonical Wnt restricting matter. Nat. Rev. Rheumatol. 13, 670–681 (2017).

    CAS 
    PubMed 

    Google Scholar 

  • 156.

    Deshmukh, V. et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage 26, 18–27 (2018).

    CAS 
    PubMed 

    Google Scholar 

  • 157.

    Yazici, Y. et al. A phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis. Osteoarthritis Cartilage 29, 654–666 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • 158.

    Deshmukh, V. et al. Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment. Osteoarthritis Cartilage 27, 1347–1360 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • 159.

    Monteagudo, S. et al. DOT1L safeguards cartilage homeostasis and protects against osteoarthritis. Nat. Commun. 8, 15889 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 160.

    Cornelis, F. M. F. et al. Increased susceptibility to develop spontaneous and post-traumatic osteoarthritis in Dot1l-deficient mice. Osteoarthritis Cartilage 27, 513–525 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • 161.

    Castaño Betancourt, M. C. et al. Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis. Proc. Natl Acad. Sci. USA 109, 8218–8223 (2012).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 162.

    Deng, Y. et al. Yap1 regulates multiple steps of chondrocyte differentiation during skeletal development and bone repair. Cell Rep. 14, 2224–2237 (2016).

    CAS 
    PubMed 

    Google Scholar 

  • 163.

    Gumbiner, B. M. & Kim, N.-G. The Hippo-YAP signaling pathway and contact inhibition of growth. J. Cell Sci. 127, 709–717 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 164.

    Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    CAS 
    PubMed 

    Google Scholar 

  • 165.

    Baker, B. M. & Chen, C. S. Deconstructing the third dimension–how 3D culture microenvironments alter cellular cues. J. Cell Sci. 125, 3015–3024 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 166.

    Caliari, S. R., Vega, S. L., Kwon, M., Soulas, E. M. & Burdick, J. A. Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments. Biomaterials 103, 314–323 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 167.

    Karystinou, A. et al. Yes-associated protein (YAP) is a negative regulator of chondrogenesis in mesenchymal stem cells. Arthritis Res. Ther. 17, 147 (2015).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 168.

    Mobasheri, A. et al. The role of metabolism in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 13, 302–311 (2017).

    CAS 
    PubMed 

    Google Scholar 

  • 169.

    Salinas, D., Mumey, B. M. & June, R. K. Physiological dynamic compression regulates central energy metabolism in primary human chondrocytes. Biomech. Model. Mechanobiol. 18, 69–77 (2019).

    PubMed 

    Google Scholar 

  • 170.

    Lehtinen, M. K. et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125, 987–1001 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • 171.

    Niehoff, A. et al. Dynamic and static mechanical compression affects Akt phosphorylation in porcine patellofemoral joint cartilage. J. Orthop. Res. 26, 616–623 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • 172.

    Holledge, M. M., Millward-Sadler, S. J., Nuki, G. & Salter, D. M. Mechanical regulation of proteoglycan synthesis in normal and osteoarthritic human articular chondrocytes–roles for α5 and αVβ5 integrins. Biorheology 45, 275–288 (2008).

    PubMed 

    Google Scholar 

  • 173.

    Delco, M. L., Bonnevie, E. D., Bonassar, L. J. & Fortier, L. A. Mitochondrial dysfunction is an acute response of articular chondrocytes to mechanical injury. J. Orthop. Res. 36, 739–750 (2018).

    CAS 
    PubMed 

    Google Scholar 

  • 174.

    Waller, K. A., Zhang, L. X. & Jay, G. D. Friction-induced mitochondrial dysregulation contributes to joint deterioration in Prg4 knockout mice. Int. J. Mol. Sci. 18, 1252 (2017).

    PubMed Central 

    Google Scholar 

  • 175.

    Bartell, L. R. et al. Mitoprotective therapy prevents rapid, strain-dependent mitochondrial dysfunction after articular cartilage injury. J. Orthop. Res. 38, 1257–1267 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • 176.

    Jutila, A. A. et al. Candidate mediators of chondrocyte mechanotransduction via targeted and untargeted metabolomic measurements. Arch. Biochem. Biophys. 545, 116–123 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 177.

    Zignego, D. L., Jutila, A. A., Gelbke, M. K., Gannon, D. M. & June, R. K. The mechanical microenvironment of high concentration agarose for applying deformation to primary chondrocytes. J. Biomech. 47, 2143–2148 (2014).

    PubMed 

    Google Scholar 

  • 178.

    Hodgkinson, T. et al. The use of nanovibration to discover specific and potent bioactive metabolites that stimulate osteogenic differentiation in mesenchymal stem cells. Sci. Adv. 7, eabb7921 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 179.

    Bonnevie, E. D. et al. Microscale frictional strains determine chondrocyte fate in loaded cartilage. J. Biomech. 74, 72–78 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 180.

    Irwin, R. M. et al. Distinct tribological endotypes of pathological human synovial fluid reveal characteristic biomarkers and variation in efficacy of viscosupplementation at reducing local strains in articular cartilage. Osteoarthritis Cartilage 28, 492–501 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 181.

    Xie, R. et al. Biomimetic cartilage-lubricating polymers regenerate cartilage in rats with early osteoarthritis. Nat. Biomed. Eng. 5, 1189–1201 (2021).

    PubMed 

    Google Scholar 

  • 182.

    Grither, W. R. & Longmore, G. D. Inhibition of tumor-microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain. Proc. Natl Acad. Sci. USA 115, E7786–E7794 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 183.

    Kumar, A., Choudhury, M. D., Ghosh, P. & Palit, P. Discoidin domain receptor 2: an emerging pharmacological drug target for prospective therapy against osteoarthritis. Pharmacol. Rep. 71, 399–408 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • 184.

    Occhetta, P. et al. Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip model. Nat. Biomed. Eng. 3, 545–557 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • 185.

    Lee, J. et al. Combinatorial screening of biochemical and physical signals for phenotypic regulation of stem cell-based cartilage tissue engineering. Sci. Adv. 6, eaaz5913 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 186.

    Wang, J., Lü, D., Mao, D. & Long, M. Mechanomics: an emerging field between biology and biomechanics. Protein Cell 5, 518–531 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 187.

    Gabriel, S. E., Crowson, C. S. & O’Fallon, W. M. Comorbidity in arthritis. J. Rheumatol. 26, 2475–2479 (1999).

    CAS 
    PubMed 

    Google Scholar 

  • 188.

    Shi, S., Man, Z., Li, W., Sun, S. & Zhang, W. Silencing of Wnt5a prevents interleukin-1β-induced collagen type II degradation in rat chondrocytes. Exp. Ther. Med. 12, 3161–3166 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 189.

    Yan, H. et al. Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc. Natl Acad. Sci. USA 113, E6199–E6208 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 190.

    Rai, M. F. et al. Applications of RNA interference in the treatment of arthritis. Transl. Res. 214, 1–16 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 191.

    Cheleschi, S. et al. Hydrostatic pressure regulates microRNA expression levels in osteoarthritic chondrocyte cultures via the Wnt/β-catenin pathway. Int. J. Mol. Sci. 18, 133 (2017).

    PubMed Central 

    Google Scholar 

  • 192.

    De Palma, A. et al. Hydrostatic pressure as epigenetic modulator in chondrocyte cultures: a study on miRNA-155, miRNA-181a and miRNA-223 expression levels. J. Biomech. 66, 165–169 (2018).

    PubMed 

    Google Scholar 

  • 193.

    Yang, X. et al. Mechanical and IL-1β responsive miR-365 contributes to osteoarthritis development by targeting histone deacetylase 4. Int. J. Mol. Sci. 17, 436 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 194.

    Stadnik, P. S. et al. Regulation of microRNA-221, -222, -21 and -27 in articular cartilage subjected to abnormal compressive forces. J. Physiol. 599, 143–155 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • 195.

    Dunn, W., DuRaine, G. & Reddi, A. H. Profiling microRNA expression in bovine articular cartilage and implications for mechanotransduction. Arthritis Rheum. 60, 2333–2339 (2009).

    PubMed 

    Google Scholar 

  • 196.

    Iliopoulos, D., Malizos, K. N., Oikonomou, P. & Tsezou, A. Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks. PLoS ONE 3, e3740 (2008).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 197.

    Song, J. et al. MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis. BBA Clin. 3, 79–89 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 198.

    Hecht, N., Johnstone, B., Angele, P., Walker, T. & Richter, W. Mechanosensitive MiRs regulated by anabolic and catabolic loading of human cartilage. Osteoarthritis Cartilage 27, 1208–1218 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • 199.

    Lolli, A., Colella, F., De Bari, C. & van Osch, G. J. V. M. Targeting anti-chondrogenic factors for the stimulation of chondrogenesis: a new paradigm in cartilage repair. J. Orthop. Res. 37, 12–22 (2019).

    PubMed 

    Google Scholar 

  • 200.

    Mohanraj, B. et al. Mechanically activated microcapsules for “on-demand” drug delivery in dynamically loaded musculoskeletal tissues. Adv. Funct. Mater. 29, 1807909 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • 201.

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

    PubMed 
    PubMed Central 

    Google Scholar 

  • 202.

    Lin, X., Bai, Y., Zhou, H. & Yang, L. Mechano-active biomaterials for tissue repair and regeneration. J. Mater. Sci. Technol. 59, 227–233 (2020).

    Google Scholar 

  • 203.

    Zhang, Y., Yu, J., Bomba, H. N., Zhu, Y. & Gu, Z. Mechanical force-triggered drug delivery. Chem. Rev. 116, 12536–12563 (2016).

    CAS 
    PubMed 

    Google Scholar 

  • 204.

    Xiao, L. et al. Hyaluronic acid-based hydrogels containing covalently integrated drug depots: implication for controlling inflammation in mechanically stressed tissues. Biomacromolecules 14, 3808–3819 (2013).

    CAS 
    PubMed 

    Google Scholar 

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