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Intervertebral disc (IVD) degeneration (IVDD) is the main cause of low back pain with major social and economic burdens; however, its underlying molecular mechanisms remain poorly defined. Here we show that the focal adhesion protein Kindlin-2 is highly expressed in the nucleus pulposus (NP), but not in the anulus fibrosus and the cartilaginous endplates, in the IVD tissues. Expression of Kindlin-2 is drastically decreased in NP cells in aged mice and severe IVDD patients. Inducible deletion of Kindlin-2 in NP cells in adult mice causes spontaneous and striking IVDD-like phenotypes in lumbar IVDs and largely accelerates progression of coccygeal IVDD in the presence of abnormal mechanical stress. Kindlin-2 loss activates Nlrp3 inflammasome and stimulates expression of IL-1β in NP cells, which in turn downregulates Kindlin-2. This vicious cycle promotes extracellular matrix (ECM) catabolism and NP cell apoptosis. Furthermore, abnormal mechanical stress reduces expression of Kindlin-2, which exacerbates Nlrp3 inflammasome activation, cell apoptosis, and ECM catabolism in NP cells caused by Kindlin-2 deficiency. In vivo blocking Nlrp3 inflammasome activation prevents IVDD progression induced by Kindlin-2 loss and abnormal mechanical stress. Of translational significance, adeno-associated virus-mediated overexpression of Kindlin-2 inhibits ECM catabolism and cell apoptosis in primary human NP cells in vitro and alleviates coccygeal IVDD progression caused by mechanical stress in rat. Collectively, we establish critical roles of Kindlin-2 in inhibiting Nlrp3 inflammasome activation and maintaining integrity of the IVD homeostasis and define a novel target for the prevention and treatment of IVDD.
Vos, T. et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396, 1204–1222 (2020).
Clouet, J. et al. Intervertebral disc regeneration: from cell therapy to the development of novel bioinspired endogenous repair strategies. Adv. Drug Deliv. Rev. 146, 306–324 (2019).
Lyu, F. J. et al. IVD progenitor cells: a new horizon for understanding disc homeostasis and repair. Nat. Rev. Rheumatol. 15, 102–112 (2019).
Frapin, L. et al. Lessons learned from intervertebral disc pathophysiology to guide rational design of sequential delivery systems for therapeutic biological factors. Adv. Drug Deliv. Rev. 149, 49–71 (2019).
Ma, K. et al. Mechanisms of endogenous repair failure during intervertebral disc degeneration. Osteoarthr. Cartil. 27, 41–48 (2019).
Risbud, M. V. & Shapiro, I. M. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat. Rev. Rheumatol. 10, 44–56 (2014).
Vergroesen, P. P. et al. Mechanics and biology in intervertebral disc degeneration: a vicious circle. Osteoarthr. Cartil. 23, 1057–1070 (2015).
Sun, Z., Costell, M. & Fassler, R. Integrin activation by talin, kindlin and mechanical forces. Nat. Cell Biol. 21, 25–31 (2019).
Plow, E. F. & Qin, J. The kindlin family of adapter proteins. Circ. Res. 124, 202–204 (2019).
Wu, C. et al. Kindlin-2 controls TGF-beta signalling and Sox9 expression to regulate chondrogenesis. Nat. Commun. 6, 7531 (2015).
Cao, H. et al. Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice. Bone Res 8, 2 (2020).
Lei, Y. et al. LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice. Bone Res 8, 37 (2020).
Wang, Y. et al. Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in mice. JCI Insight 4, e131692 (2019).
Sun, Y. et al. Kindlin-2 association with rho GDP-dissociation inhibitor alpha suppresses Rac1 activation and podocyte injury. J. Am. Soc. Nephrol. 28, 3545–3562 (2017).
Wei, X. et al. Kindlin-2 mediates activation of TGF-beta/Smad signaling and renal fibrosis. J. Am. Soc. Nephrol. 24, 1387–1398 (2013).
Zhang, Z. et al. Kindlin-2 is essential for preserving integrity of the developing heart and preventing ventricular rupture. Circulation 139, 1554–1556 (2019).
Qi, L. et al. Kindlin-2 suppresses transcription factor GATA4 through interaction with SUV39H1 to attenuate hypertrophy. Cell Death Dis. 10, 890 (2019).
Gao, H. et al. Lipoatrophy and metabolic disturbance in mice with adipose-specific deletion of kindlin-2. JCI Insight 4, e128405 (2019).
Zhu, K. et al. Kindlin-2 modulates MafA and beta-catenin expression to regulate beta-cell function and mass in mice. Nat. Commun. 11, 484 (2020).
He, X. et al. Kindlin-2 deficiency induces fatal intestinal obstruction in mice. Theranostics 10, 6182–6200 (2020).
Fu, X. et al. Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice. Signal Transduct. Target Ther. 5, 297 (2020).
Qin, L. et al. Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes. Commun. Biol. 4, 402 (2021).
Tam, V. et al. Histological and reference system for the analysis of mouse intervertebral disc. J. Orthop. Res 36, 233–243 (2018).
Ji, M. L. et al. Preclinical development of a microRNA-based therapy for intervertebral disc degeneration. Nat. Commun. 9, 5051 (2018).
Chen, F. et al. Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1beta/NF-kappaB-NLRP3 inflammasome positive feedback loop. Bone Res. 8, 10 (2020).
Lin, H. et al. Edaravone ameliorates compression-induced damage in rat nucleus pulposus cells. Life Sci. 189, 76–83 (2017).
Yang, S. et al. Intervertebral disc ageing and degeneration: the antiapoptotic effect of oestrogen. Ageing Res Rev. 57, 100978 (2020).
Chen, S. et al. TGF-beta signaling in intervertebral disc health and disease. Osteoarthr. Cartil. 27, 1109–1117 (2019).
Mangan, M. S. J. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Disco. 17, 588–606 (2018).
Swanson, K. V., Deng, M. & Ting, J. P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477–489 (2019).
Hong, J. et al. Bromodomain-containing protein 4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity in NP cells. J. Cell Physiol. 235, 5736–5749 (2020).
Tang, P. et al. Honokiol alleviates the degeneration of intervertebral disc via suppressing the activation of TXNIP-NLRP3 inflammasome signal pathway. Free Radic. Biol. Med. 120, 368–379 (2018).
Zhao, Y. et al. Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation. Theranostics 10, 7015–7033 (2020).
Holguin, N. et al. The aging mouse partially models the aging human spine: lumbar and coccygeal disc height, composition, mechanical properties, and Wnt signaling in young and old mice. J. Appl. Physiol. (1985) 116, 1551–1560 (2014).
Bian, Q. et al. Mechanosignaling activation of TGFbeta maintains intervertebral disc homeostasis. Bone Res. 5, 17008 (2017).
Chen, S. et al. Mesenchymal stem cells protect nucleus pulposus cells from compression-induced apoptosis by inhibiting the mitochondrial pathway. Stem Cells Int. 2017, 9843120 (2017).
Saleem, S. et al. Lumbar disc degenerative disease: disc degeneration symptoms and magnetic resonance image findings. Asian Spine J. 7, 322–334 (2013).
Wang, K. et al. Ligustilide alleviated IL-1β induced apoptosis and extracellular matrix degradation of nucleus pulposus cells and attenuates intervertebral disc degeneration in vivo. Int. Immunopharmacol. 69, 398–407 (2019).
Cheng, X. et al. Circular RNA VMA21 protects against intervertebral disc degeneration through targeting miR-200c and X linked inhibitor-of-apoptosis protein. Ann. Rheum. Dis. 77, 770–779 (2018).
Wu, A. et al. Global low back pain prevalence and years lived with disability from 1990 to 2017: estimates from the Global Burden of Disease Study 2017. Ann. Transl. Med. 8, 299 (2020).
Roberts, S. Disc morphology in health and disease. Biochem Soc. Trans. 30, 864–869 (2002).
Rodrigues-Pinto, R., Richardson, S. M. & Hoyland, J. A. An understanding of intervertebral disc development, maturation and cell phenotype provides clues to direct cell-based tissue regeneration therapies for disc degeneration. Eur. Spine J. 23, 1803–1814 (2014).
Pfirrmann, C. W. et al. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Philos. Pa 1976) 26, 1873–1878 (2001).
Hu, B. et al. Heme oxygenase-1 attenuates IL-1beta induced alteration of anabolic and catabolic activities in intervertebral disc degeneration. Sci. Rep. 6, 21190 (2016).
Henry, S. P. et al. Generation of aggrecan-CreERT2 knockin mice for inducible Cre activity in adult cartilage. Genesis 47, 805–814 (2009).
Oh, C. D. et al. Rho-associated kinase inhibitor immortalizes rat nucleus pulposus and annulus fibrosus cells: establishment of intervertebral disc cell lines with novel approaches. Spine (Philos. Pa 1976) 41, E255–E261 (2016).
Chen, S. et al. Moderate fluid shear stress regulates heme oxygenase-1 expression to promote autophagy and ECM homeostasis in the nucleus pulposus cells. Front Cell Dev. Biol. 8, 127 (2020).
Liao, Z. et al. Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo. Theranostics 9, 4084–4100 (2019).
Ma, K. G. et al. Autophagy is activated in compression-induced cell degeneration and is mediated by reactive oxygen species in nucleus pulposus cells exposed to compression. Osteoarthr. Cartil. 21, 2030–2038 (2013).
He, R. et al. HIF1A Alleviates compression-induced apoptosis of nucleus pulposus derived stem cells via upregulating autophagy. Autophagy 17, 3338–3360 (2021).
Han, B. et al. A simple disc degeneration model induced by percutaneous needle puncture in the rat tail. Spine (Philos. Pa 1976) 33, 1925–1934 (2008).
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