AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Bone Research Article
PDF (7.6 MB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Original Article | Open Access

Kindlin-2 inhibits Nlrp3 inflammasome activation in nucleus pulposus to maintain homeostasis of the intervertebral disc

Sheng Chen1,2,, Xiaohao Wu2,, Yumei Lai3, Di Chen4, Xiaochun Bai5, Sheng Liu1, Yongchao Wu1, Mingjue Chen2, Yuxiao Lai6, Huiling Cao2( ), Zengwu Shao1( ), Guozhi Xiao2 ( )
Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen 518055, China
Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA
Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Centre for Translational Medicine Research and Development, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China

These authors contributed equally: Sheng Chen, Xiaohao Wu

Show Author Information

Abstract

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.

References

1

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).
Crossref Google Scholar
2

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).
Crossref Google Scholar
3

Lyu, F. J. et al. IVD progenitor cells: a new horizon for understanding disc homeostasis and repair. Nat. Rev. Rheumatol. 15, 102–112 (2019).
Crossref Google Scholar
4

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).
Crossref Google Scholar
5

Ma, K. et al. Mechanisms of endogenous repair failure during intervertebral disc degeneration. Osteoarthr. Cartil. 27, 41–48 (2019).
Crossref Google Scholar
6

Risbud, M. V. & Shapiro, I. M. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat. Rev. Rheumatol. 10, 44–56 (2014).
Crossref Google Scholar
7

Vergroesen, P. P. et al. Mechanics and biology in intervertebral disc degeneration: a vicious circle. Osteoarthr. Cartil. 23, 1057–1070 (2015).
Crossref Google Scholar
8

Sun, Z., Costell, M. & Fassler, R. Integrin activation by talin, kindlin and mechanical forces. Nat. Cell Biol. 21, 25–31 (2019).
Crossref Google Scholar
9

Plow, E. F. & Qin, J. The kindlin family of adapter proteins. Circ. Res. 124, 202–204 (2019).
Crossref Google Scholar
10

Wu, C. et al. Kindlin-2 controls TGF-beta signalling and Sox9 expression to regulate chondrogenesis. Nat. Commun. 6, 7531 (2015).
Crossref Google Scholar
11

Cao, H. et al. Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice. Bone Res 8, 2 (2020).
Crossref Google Scholar
12

Lei, Y. et al. LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice. Bone Res 8, 37 (2020).
Crossref Google Scholar
13

Wang, Y. et al. Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in mice. JCI Insight 4, e131692 (2019).
Crossref Google Scholar
14

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).
Crossref Google Scholar
15

Wei, X. et al. Kindlin-2 mediates activation of TGF-beta/Smad signaling and renal fibrosis. J. Am. Soc. Nephrol. 24, 1387–1398 (2013).
Crossref Google Scholar
16

Zhang, Z. et al. Kindlin-2 is essential for preserving integrity of the developing heart and preventing ventricular rupture. Circulation 139, 1554–1556 (2019).
Crossref Google Scholar
17

Qi, L. et al. Kindlin-2 suppresses transcription factor GATA4 through interaction with SUV39H1 to attenuate hypertrophy. Cell Death Dis. 10, 890 (2019).
Crossref Google Scholar
18

Gao, H. et al. Lipoatrophy and metabolic disturbance in mice with adipose-specific deletion of kindlin-2. JCI Insight 4, e128405 (2019).
Crossref Google Scholar
19

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).
Crossref Google Scholar
20

He, X. et al. Kindlin-2 deficiency induces fatal intestinal obstruction in mice. Theranostics 10, 6182–6200 (2020).
Crossref Google Scholar
21

Fu, X. et al. Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice. Signal Transduct. Target Ther. 5, 297 (2020).
Crossref Google Scholar
22

Qin, L. et al. Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes. Commun. Biol. 4, 402 (2021).
Crossref Google Scholar
23

Tam, V. et al. Histological and reference system for the analysis of mouse intervertebral disc. J. Orthop. Res 36, 233–243 (2018).
Crossref Google Scholar
24

Ji, M. L. et al. Preclinical development of a microRNA-based therapy for intervertebral disc degeneration. Nat. Commun. 9, 5051 (2018).
Crossref Google Scholar
25

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).
Crossref Google Scholar
26

Lin, H. et al. Edaravone ameliorates compression-induced damage in rat nucleus pulposus cells. Life Sci. 189, 76–83 (2017).
Crossref Google Scholar
27

Yang, S. et al. Intervertebral disc ageing and degeneration: the antiapoptotic effect of oestrogen. Ageing Res Rev. 57, 100978 (2020).
Crossref Google Scholar
28

Chen, S. et al. TGF-beta signaling in intervertebral disc health and disease. Osteoarthr. Cartil. 27, 1109–1117 (2019).
Crossref Google Scholar
29

Mangan, M. S. J. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Disco. 17, 588–606 (2018).
Crossref Google Scholar
30

Swanson, K. V., Deng, M. & Ting, J. P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477–489 (2019).
Crossref Google Scholar
31

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).
Crossref Google Scholar
32

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).
Crossref Google Scholar
33

Zhao, Y. et al. Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation. Theranostics 10, 7015–7033 (2020).
Crossref Google Scholar
34

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).
Crossref Google Scholar
35

Bian, Q. et al. Mechanosignaling activation of TGFbeta maintains intervertebral disc homeostasis. Bone Res. 5, 17008 (2017).
Crossref Google Scholar
36

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).
Crossref Google Scholar
37

Saleem, S. et al. Lumbar disc degenerative disease: disc degeneration symptoms and magnetic resonance image findings. Asian Spine J. 7, 322–334 (2013).
Crossref Google Scholar
38

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).
Crossref Google Scholar
39

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).
Crossref Google Scholar
40

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).
Crossref Google Scholar
41

Roberts, S. Disc morphology in health and disease. Biochem Soc. Trans. 30, 864–869 (2002).
Crossref Google Scholar
42

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).
Crossref Google Scholar
43

Pfirrmann, C. W. et al. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Philos. Pa 1976) 26, 1873–1878 (2001).
Crossref Google Scholar
44

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).
Crossref Google Scholar
45

Henry, S. P. et al. Generation of aggrecan-CreERT2 knockin mice for inducible Cre activity in adult cartilage. Genesis 47, 805–814 (2009).
Crossref Google Scholar
46

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).
Crossref Google Scholar
47

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).
Crossref Google Scholar
48

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).
Crossref Google Scholar
49

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).
Crossref Google Scholar
50

He, R. et al. HIF1A Alleviates compression-induced apoptosis of nucleus pulposus derived stem cells via upregulating autophagy. Autophagy 17, 3338–3360 (2021).
Crossref Google Scholar
51

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).
Crossref Google Scholar
Bone Research
Volume 10,
December 2022
Article number: 5
DOI: 10.1038/s41413-021-00179-5
Cite this article:
Chen S, Wu X, Lai Y, et al. Kindlin-2 inhibits Nlrp3 inflammasome activation in nucleus pulposus to maintain homeostasis of the intervertebral disc. Bone Research, 2022, 10: 5. https://doi.org/10.1038/s41413-021-00179-5

193

Views

2

Downloads

54

Crossref

51

Web of Science

57

Scopus

Altmetrics
Received: 01 June 2021
Revised: 14 August 2021
Accepted: 09 September 2021
Published: 10 January 2022
© The Author(s) 2022

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Return