Wnt/β‑catenin signaling may induce senescence of chondrocytes in osteoarthritis

Li,Weijun; Xiong,Yan; Chen,Weiping; Wu,Lidong

doi:10.3892/etm.2020.9022

Wnt/β‑catenin signaling may induce senescence of chondrocytes in osteoarthritis

Authors:
- Weijun Li
- Yan Xiong
- Weiping Chen
- Lidong Wu
View Affiliations

Affiliations: Department of Orthopedics Surgery, The Second Afﬁliated Hospital of Medical College, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
Published online on: July 17, 2020 https://doi.org/10.3892/etm.2020.9022
Pages: 2631-2638
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Osteoarthritis (OA) is an autoimmune disease associated with increasing age. Typically, chondrocyte senescence is believed to serve an important role in the development and progression of OA. However, the specific mechanisms underlying chondrocyte senescence have not been fully addressed. The present study hypothesized that the Wnt/β‑catenin signaling may represent a major regulator of chondrocyte senescence. In addition, the acetylated levels of p53 and sirtuin‑1 (SIRT‑1) were examined as putative markers for chondrocyte senescence, since activation of p53 is considered an important step in the regulation of senescence. The Wnt/β‑catenin signaling pathway was activated using LiCl and inhibited using the Wnt signaling pathway inhibitor, dickkopf‑1 (DKK1) in order to evaluate the role of this pathway in the development of OA. Senescent cells were detected using the senescence‑associated indicator acidic senescence‑associated β‑galactosidase (SA‑β‑gal). The effects of p53 and p16 on chondrocyte senescence were assessed via activation of Wnt/β‑catenin signaling using Wnt‑1. In addition, β‑catenin was transfected into chondrocytes to induce activation of the Wnt/β‑catenin signaling pathway. Finally, a rabbit model of OA was used to assess whether the observed effects on the Wnt/β‑catenin signaling pathway and the induction of chondrocyte senescence were perpetuated. Activation of Wnt/β‑catenin signaling increased the expression levels of SA‑β‑gal, p53, p16 and acetylated p53. Transfection of β‑catenin in chondrocytes increased the expression levels of acetylated p53 and decreased the expression levels of SIRT‑1, which in turn deacetylated p53 and modulated its activity. Finally, the role of the Wnt/β‑catenin signaling pathway was confirmed in the development of OA using a rabbit model with this condition. The present study suggested that activation of the Wnt/β‑catenin signaling pathway promoted chondrocyte senescence, through downregulation of SIRT‑1 and increased the expression of acetylated p53.

View Figures

View References

1	Garstang SV and Stitik TP: Osteoarthritis: Epidemiology, risk factors, and pathophysiology. Am J Phys Med Rehabil. 85 (11 Suppl):S2–S11; quiz S12-S14. 2006.PubMed/NCBI View Article : Google Scholar
2	Arden N and Nevitt MC: Osteoarthritis: Epidemiology. Best Pract Res Clin Rheumatol. 20:3–25. 2006.PubMed/NCBI View Article : Google Scholar
3	Vinatier C, Domínguez E, Guicheux J and Caramés B: Role of the inflammation-autophagy-senescence integrative network in osteoarthritis. Front Physiol. 25(706)2018.PubMed/NCBI View Article : Google Scholar
4	Erusalimsky JD and Kurz DJ: Cellular senescence in vivo: Its relevance in ageing and cardiovascular disease. Exp Gerontol. 40:634–642. 2005.PubMed/NCBI View Article : Google Scholar
5	McCulloch K, Litherland GJ and Rai TS: Cellular senescence in osteoarthritis pathology. Aging Cell. 16:210–218. 2017.PubMed/NCBI View Article : Google Scholar
6	Price JS, Waters JG, Darrah C, Pennington C, Edwards DR, Donell ST and Clark IM: The role of chondrocyte senescence in osteoarthritis. Aging Cell. 1:57–65. 2002.PubMed/NCBI View Article : Google Scholar
7	Xu M, Bradley EW, Weivoda MM, Hwang SM, Pirtskhalava T, Decklever T, Curran GL, Ogrodnik M, Jurk D, Johnson KO, et al: Transplanted senescent cells induce an osteoarthritis-like condition in mice. J Gerontol A Biol Sci Med Sci. 72:780–785. 2017.PubMed/NCBI View Article : Google Scholar
8	Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, Chung JW, Kim DH, Poon Y, David N, et al: Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 23:775–781. 2017.PubMed/NCBI View Article : Google Scholar
9	Johnson ML and Kamel MA: The wnt signaling pathway and bone metabolism. Curr Opin Rheumatol. 19:376–382. 2007.PubMed/NCBI View Article : Google Scholar
10	Schett G, Zwerina J and David JP: The role of wnt proteins in arthritis. Nat Clin Pract Rheumatol. 4:473–480. 2008.PubMed/NCBI View Article : Google Scholar
11	Corr M: Wnt-beta-catenin signaling in the pathogenesis of osteoarthritis. Nat Clin Pract Rheumatol. 4:550–556. 2008.PubMed/NCBI View Article : Google Scholar
12	Yuasa T, Otani T, Koike T, Iwamoto M and Enomoto-Iwamoto M: Wnt/beta-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: Its possible role in joint degeneration. Lab Invest. 88:264–274. 2008.PubMed/NCBI View Article : Google Scholar
13	Tamamura Y, Otani T, Kanatani N, Koyama E, Kitagaki J, Komori T, Yamada Y, Costantini F, Wakisaka S, Pacifici M, et al: Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem. 13:19185–19195. 2005.PubMed/NCBI View Article : Google Scholar
14	Zhu M, Tang D, Wu Q, Hao S, Chen M, Xie C, Rosier RN, O'Keefe RJ, Zuscik M and Chen D: Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res. 24:12–21. 2009.PubMed/NCBI View Article : Google Scholar
15	Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 3:469–480. 2006.PubMed/NCBI View Article : Google Scholar
16	Gregory CA, Singh H, Perry AS and Prockop DJ: The Wnt signaling inhibitor dickkopf-1 is required for reentry into the cell cycle of human adult stem cells from bone marrow. J Biol Chem. 278:28067–28078. 2003.PubMed/NCBI View Article : Google Scholar
17	Hiyama A, Sakai D, Risbud MV, Tanaka M, Arai F, Abe K and Mochida J: Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling-induced matrix metalloproteinase expression. Arthritis Rheum. 62:3036–3047. 2010.PubMed/NCBI View Article : Google Scholar
18	Song P, Zheng JX, Liu JZ, Xu J, Wu LY, Liu C, Zhu Q and Wang Y: Effect of the Wnt1/β-catenin signalling pathway on human embryonic pulmonary fibroblasts. Mol Med Rep. 10:1030–1036. 2014.
19	Li WJ, Tang LP, Xiong Y, Chen WP, Zhou XD, Ding QH and Wu LD: A possible mechanism in DHEA-mediated protection against osteoarthritis. Steroids. 89:20–26. 2014.PubMed/NCBI View Article : Google Scholar
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
21	Mankin HJ, Dorfman H, Lippiello L and Zarins A: Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J Bone Joint Surg Am. 53:523–537. 1971.PubMed/NCBI
22	Wojdasiewicz P, Poniatowski ŁA and Szukiewicz D: The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm. 2014(561459)2014.PubMed/NCBI View Article : Google Scholar
23	Heinecke LF, Grzanna MW, Au AY, Mochal CA, Rashmir-Raven A and Frondoza CG: Inhibition of cyclooxygenase-2 expression and prostaglandin E2 production in chondrocytes by avocado soybean unsaponifiables and epigallocatechin gallate. Osteoarthritis Cartilage. 18:220–227. 2010.PubMed/NCBI View Article : Google Scholar
24	Mitchell PG, Magna HA, Reeves LM, Lopresti-Morrow LL, Yocum SA, Rosner PJ, Geoghegan KF and Hambor JE: Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest. 1:761–768. 1996.PubMed/NCBI View Article : Google Scholar
25	Ye X, Zerlanko B, Kennedy A, Banumathy G, Zhang R and Adams PD: Downregulation of wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. Mol Cell. 27:183–196. 2007.PubMed/NCBI View Article : Google Scholar
26	Campisi J: Senescent cells, tumor suppression, and organismal aging: Good citizens, bad neighbors. Cell. 120:513–522. 2005.PubMed/NCBI View Article : Google Scholar
27	Reya T and Clevers H: Wnt signalling in stem cells and cancer. Nature. 14:843–850. 2005.PubMed/NCBI View Article : Google Scholar
28	Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel D, Kuo CJ, et al: Augmented Wnt signaling in a mammalian model of accelerated aging. Science. 10:803–806. 2007.PubMed/NCBI View Article : Google Scholar
29	Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ and Lowe SW: Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol. 22:3497–3508. 2002.PubMed/NCBI View Article : Google Scholar
30	Lee SW, Fang L, Igarashi M, Ouchi T, Lu KP and Aaronson SA: Sustained activation of Ras/Raf/mitogen-activated protein kinase cascade by the tumor suppressor p53. Proc Natl Acad Sci USA. 18:8302–8305. 2000.PubMed/NCBI View Article : Google Scholar
31	Narita M, Nũnez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ and Lowe SW: Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 13:703–716. 2003.PubMed/NCBI View Article : Google Scholar
32	Sasaki T, Maier B, Bartke A and Scrable H: Progressive loss of SIRT1 with cell cycle withdrawal. Aging Cell. 5:413–4122. 2006.PubMed/NCBI View Article : Google Scholar
33	Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG and Kouzarides T: Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 15:2383–2396. 2002.PubMed/NCBI View Article : Google Scholar
34	Vigneron A and Vousden KH: p53, ROS and senescence in the control of aging. Aging (Albany NY). 2:471–474. 2010.PubMed/NCBI View Article : Google Scholar