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 International Journal of Oral Science Article
PDF (7.7 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 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice

Yumei Lai1,, Wei Zheng2,, Minghao Qu3,, Christopher C. Xiao1, Sheng Chen3,4, Qing Yao3, Weiyuan Gong3, Chu Tao3, Qinnan Yan3, Peijun Zhang3, Xiaohao Wu3( ), Guozhi Xiao3 ( )
Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA
Department of Orthopaedic Center, Xinjiang Production and Construction Corps Hospital, Urumqi, 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, China
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

These authors contributed equally: Yumei Lai, Wei Zheng, Minghao Qu

Show Author Information

Abstract

The progressive destruction of condylar cartilage is a hallmark of the temporomandibular joint (TMJ) osteoarthritis (OA); however, its mechanism is incompletely understood. Here, we show that Kindlin-2, a key focal adhesion protein, is strongly detected in cells of mandibular condylar cartilage in mice. We find that genetic ablation of Kindlin-2 in aggrecan-expressing condylar chondrocytes induces multiple spontaneous osteoarthritic lesions, including progressive cartilage loss and deformation, surface fissures, and ectopic cartilage and bone formation in TMJ. Kindlin-2 loss significantly downregulates the expression of aggrecan, Col2a1 and Proteoglycan 4 (Prg4), all anabolic extracellular matrix proteins, and promotes catabolic metabolism in TMJ cartilage by inducing expression of Runx2 and Mmp13 in condylar chondrocytes. Kindlin-2 loss decreases TMJ chondrocyte proliferation in condylar cartilages. Furthermore, Kindlin-2 loss promotes the release of cytochrome c as well as caspase 3 activation, and accelerates chondrocyte apoptosis in vitro and TMJ. Collectively, these findings reveal a crucial role of Kindlin-2 in condylar chondrocytes to maintain TMJ homeostasis.

References

1

Wang, Z. et al. Loss of Fgfr1 in chondrocytes inhibits osteoarthritis by promoting autophagic activity in temporomandibular joint. J. Biol. Chem. 293, 8761–8774 (2018).
Crossref Google Scholar
2

Bianchi, J. et al. Osteoarthritis of the temporomandibular joint can be diagnosed earlier using biomarkers and machine learning. Sci. Rep. 10, 8012 (2020).
Crossref Google Scholar
3

Liu, Q. et al. Initiation and progression of dental-stimulated temporomandibular joints osteoarthritis. Osteoarthr. Cartil. 29, 633–642 (2021).
Crossref Google Scholar
4
Monasterio, G. et al. in Temporomandibular Joint Pathology—Current Approaches and Understanding. (IntechOpen, London, 2018) https://doi.org/10.5772/intechopen.72496.
Crossref
5

Zhao, Y. P. et al. Investigation of the clinical and radiographic features of osteoarthrosis of the temporomandibular joints in adolescents and young adults. Oral. Surg. Oral. Med Oral. Pathol. Oral. Radio. Endod. 111, e27–e34 (2011).
Crossref Google Scholar
6

Song, H. et al. Long-term changes of temporomandibular joint osteoarthritis on computed tomography. Sci. Rep. 10, 6731 (2020).
Crossref Google Scholar
7

Lu, K. et al. Molecular signaling in temporomandibular joint osteoarthritis. J. Orthop. Translation 32, 21–27 (2022).
Crossref Google Scholar
8

Yang, H. et al. MTORC1 coordinates the autophagy and apoptosis signaling in articular chondrocytes in osteoarthritic temporomandibular joint. Autophagy 16, 1–18 (2019).
Crossref Google Scholar
9

Jobard, F. et al. Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome. Hum. Mol. Genet. 12, 925–935 (2003).
Crossref Google Scholar
10

Svensson, L. et al. Leukocyte adhesion deficiency-Ⅲ is caused by mutations in KINDLIN3 affecting integrin activation. Nat. Med. 15, 306–312 (2009).
Crossref Google Scholar
11

Montanez, E. et al. Kindlin-2 controls bidirectional signaling of integrins. Genes Dev. 22, 1325–1330 (2008).
Crossref Google Scholar
12

Rognoni, E., Ruppert, R. & Fassler, R. The kindlin family: functions, signaling properties and implications for human disease. J. Cell Sci. 129, 17–27 (2016).
Crossref Google Scholar
13

Calderwood, D. A., Campbell, I. D. & Critchley, D. R. Talins and kindlins: partners in integrin-mediated adhesion. Nat. Rev. Mol. Cell Biol. 14, 503–517 (2013).
Crossref Google Scholar
14

Bottcher, R. T. et al. Kindlin-2 recruits paxillin and Arp2/3 to promote membrane protrusions during initial cell spreading. J. Cell Biol. 216, 3785–3798 (2017).
Crossref Google Scholar
15

Wei, X. et al. Smurf1 inhibits integrin activation by controlling Kindlin-2 ubiquitination and degradation. J. Cell Biol. 216, 1455–1471 (2017).
Crossref Google Scholar
16

Li, H. et al. Structural basis of kindlin-mediated integrin recognition and activation. Proc. Natl Acad. Sci. USA 114, 9349–9354 (2017).
Crossref Google Scholar
17

Hirbawi, J. et al. The extreme C-terminal region of kindlin-2 is critical to its regulation of integrin activation. J. Biol. Chem. 292, 14258–14269 (2017).
Crossref Google Scholar
18

Ussar, S. et al. The Kindlins: subcellular localization and expression during murine development. Exp. Cell Res. 312, 3142–3151 (2006).
Crossref Google Scholar
19

Kern, J. S. et al. Chronic colitis due to an epithelial barrier defect: the role of kindlin-1 isoforms. J. Pathol. 213, 462–470 (2007).
Crossref Google Scholar
20

He, Y. et al. Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification. Am. J. Pathol. 178, 975–982 (2011).
Crossref Google Scholar
21

Zhan, J. et al. Kindlin-2 expression in adult tissues correlates with their embryonic origins. Sci. China Life Sci. 57, 690–697 (2014).
Crossref Google Scholar
22

Cao, H. et al. Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice. Bone Res. 8, 2 (2020).
Crossref Google Scholar
23

Chen, S. et al. Kindlin-2 inhibits Nlrp3 inflammasome activation in nucleus pulposus to maintain homeostasis of the intervertebral disc. Bone Res. 10, https://doi.org/10.1038/s41413-021-00179-5 (2022).
Crossref Google Scholar
24

Fu, X. et al. Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice. Signal. Transduct Target. Ther. 5, 297 (2020).
Crossref Google Scholar
25

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
26

Gao, H. et al. Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice. Nat. Commun. 13, 1025 (2022).
Crossref Google Scholar
27

Guo, L. et al. Kindlin-2 regulates mesenchymal stem cell differentiation through control of YAP1/TAZ. J. Cell Biol. 217, 1431–1451 (2018).
Crossref Google Scholar
28

Guo, L. et al. Kindlin-2 links mechano-environment to proline synthesis and tumor growth. Nat. Commun. 10, 845 (2019).
Crossref Google Scholar
29

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
30

Wu, C. et al. Kindlin-2 controls TGF-beta signalling and Sox9 expression to regulate chondrogenesis. Nat. Commun. 6, 7531 (2015).
Crossref Google Scholar
31

Wu, X. et al. Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis. Nat. Aging 2, 332–347 (2022).
Crossref Google Scholar
32

Wu, X. et al. Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice. J. Orthop. Translation 32, 41–48 (2022).
Crossref Google Scholar
33

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
34

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
35

Chen, D. et al. Runx2 plays a central role in osteoarthritis development. J. Orthop. Transl. 23, 132–139 (2020).
Crossref Google Scholar
36

Wang, X. et al. Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage. Osteoarthr. Cartil. 12, 963–973 (2004).
Crossref Google Scholar
37

Porter, A. G. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 6, 99–104 (1999).
Crossref Google Scholar
38

Shane Anderson, A. & Loeser, R. F. Why is osteoarthritis an age-related disease? Best. Pr. Res. Clin. Rheumatol. 24, 15–26 (2010).
Crossref Google Scholar
39

Hui, T. et al. Activation of beta-catenin signaling in aggrecan-expressing cells in temporomandibular joint causes osteoarthritis-like defects. Int. J. Oral. Sci. 10, 13 (2018).
Crossref Google Scholar
40

Wang, M. et al. Activation of β-catenin signalling leads to temporomandibular joint defects. Eur. Cell Mater. 23, 223–235 (2014).
Crossref Google Scholar
41

Hunter, D. J. & Bierma-Zeinstra, S. Osteoarthritis. Lancet 393, 1745–1759 (2019).
Crossref Google Scholar
42

Yadav, S. et al. Temporomandibular joint disorders in older adults. J. Am. Geriatr. Soc. 66, 1213–1217 (2018).
Crossref Google Scholar
43

Yang, H. et al. Inhibition of Ihh reverses temporomandibular joint osteoarthritis via a PTH1R signaling dependent mechanism. Int. J. Mol. Sci. 20, 3797 (2019).
Crossref Google Scholar
44

Wang, Y. et al. Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in mice. JCI Insight 4, e131692 (2019).
Crossref Google Scholar
45

Qin, L. et al. Molecular mechanosensors in osteocytes. Bone Res. 8, 23 (2020).
Crossref Google Scholar
46

Qin, L. et al. Roles of mechanosensitive channel Piezo1/2 proteins in skeleton and other tissues. Bone Res. 9, 44 (2021).
Crossref Google Scholar
47

Li, J. et al. Metformin limits osteoarthritis development and progression through activation of AMPK signalling. Ann. Rheum. Dis. 79, 635–645 (2020).
Crossref Google Scholar
48

Kuchler-Bopp, S. et al. Temporomandibular joint damage in K/BxN arthritic mice. Int. J. Oral. Sci. 12, 5 (2020).
Crossref Google Scholar
49

Gao, H. et al. Pinch loss ameliorates obesity, glucose intolerance, and fatty liver by modulating adipocyte apoptosis in mice. Diabetes 70, 2492–2505 (2021).
Crossref Google Scholar
50

Lei, Y. et al. LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice. Bone Res. 8, 37 (2020).
Crossref Google Scholar
51

Yan, Q. et al. Loss of phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c) in mesenchymal stem cells leads to osteopenia by impairing bone remodeling. J. Biol. Chem. 298, 101639 (2022).
Crossref Google Scholar
International Journal of Oral Science
Volume 14,
2022
Article number: 33
DOI: 10.1038/s41368-022-00185-1
Cite this article:
Lai Y, Zheng W, Qu M, et al. Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice. International Journal of Oral Science, 2022, 14: 33. https://doi.org/10.1038/s41368-022-00185-1

110

Views

0

Downloads

17

Crossref

15

Web of Science

15

Scopus

Altmetrics
Accepted: 28 May 2022
Published: 04 July 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