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

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.

SIRT1 restoration enhances chondrocyte autophagy in osteoarthritis through PTEN-mediated EGFR ubiquitination

“…Our experimental data also corroborated that SIRT1 restoration also relieved metabolic imbalance, extracellular matrix degradation and augmented chondrocyte autophagy in OA-like mice or microenvironment. Consistent evidences have reported that SIRT1 overexpression led to decreased apoptotic rates of chondrocytes [ 20 ], and SIRT1 knockdown may result in chondrocyte senescence [ 21 ]. It has been found that improved extracellular matrix degradation of IL-1β-induced chondrocytes can be led by downregulated MMP-13 and ADAMTS-5 [ 22 ].…”

Co-Modification of Beta-Catenin and Sex Determining Region Y-Box9 Genes Regulates the Chondrogenesis of Human Adipose Tissue Derived Stem Cells

“…It was also found that Sox9 overexpression could inhibit the level of β-catenin during cartilage repair in vivo [26] . Therefore, the mutual inhibition between Sox9 expression and classical Wnt/β-catenin signaling pathway indicates that chondrocyte differentiation may be regulated by a positive feedback loop mechanism: inhibition of classical Wnt signaling pathway causes Sox9 expression; Sox9 further inhibited Wnt/β-catenin signal and osteogenic differentiation, thus promoting the complete differentiation of chondrocytes [27] .…”

Dickkopf‑3 and β‑catenin play opposite roles in the Wnt/β‑catenin pathway during the abnormal subchondral bone formation of human knee osteoarthritis

“…Human β-catenin protein is an 88-kDa cytoskeletal protein, 781-amino acid long, encoded by the catenin beta-1 gene (CTNNBI) and located on the 3p21 human chromosome ( 21 ). Numerous studies have shown that β-catenin is a major signaling molecule in the Wnt signaling pathway ( 22 - 24 ). Wnt signaling pathway activation depends on β-catenin expression levels in the cell ( Fig.…”