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Research Paper|Volume 11, Issue 24|pp 12793—12809

Loss of Klotho contributes to cartilage damage by derepression of canonical Wnt/β-catenin signaling in osteoarthritis mice

Yanqing Gu1, Kewei Ren2, Liming Wang1,3,4, Qingqiang Yao1,3,4
  • 1Department of Orthopedics, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
  • 2Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical School of Southeast University, Jiangyin, China
  • 3Cartilage Regeneration Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
  • 4Digital Medicine Institute, Nanjing Medical University, Nanjing, Jiangsu, China
* Equal contribution and Co-first authors
Received: March 29, 2019Accepted: December 5, 2019Published: December 30, 2019
https://doi.org/10.18632/aging.102603

Copyright © 2019 Gu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Caducity is known to be an independent risk factor in osteoarthritis (OA), yet the molecular basis behind caducity and OA remains unclear. Klotho, an anti-caducity protein, is an endogenous antagonist of the transduction of Wnt/β-catenin signal which can stimulate the articular cartilage degradation, indicating that deficiency in Klotho may increase Wnt/β-catenin activity and consequently accelerate the development of OA. We found that expression of Klotho was markedly higher in normal mouse cartilage than in the OA model, and in this model the activity of Wnt/β-catenin and its target gene was up-regulated. Decrease in Klotho expression was closely associated with the increase of β-catenin in OA, indicating that there was a negative correlation between Klotho and Wnt signal transduction. In the vitro and in vivo experiments, Klotho was found to bind to multiple Wnt, including Wnt1, Wnt4 and Wnt7a. It was additionally found that cyclic tenisle strain (CTS) inhibited the expression of Klotho and activated β-catenin. On the contrary, over-expression of Klotho would reduce the degradation of articular cartilage induced by CTS. These results suggest that Klotho is an antagonist of endogenous Wnt/β-catenin activity. In OA cartilage, decrease in expression of Klotho can activate Wnt/β-catenin signal transduction and consequently induce cartilage injury.