AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice

Sheng Zhou,Qiting Ge,Yi Cao,Zhihong Xu,Huajian Teng,Liang Chen,Dongquan Shi,Huangxian Ju,Shuai Chen,Qing Jiang,Jianxin Li,Jin Dai,Wanli Lu,Dongyang Chen,Jinzhong Qin

doi:10.1038/srep43245

Abstract

Osteoarthritis (OA) is a progressive degenerative disease of the joints that is associated with both joint injury and ageing. Here, we investigated the role of the energy sensor AMP-activated protein kinase (AMPK) in maintaining a healthy state of articular cartilage and in OA development. Using cartilage-specific, tamoxifen-inducible AMPKα1 conditional knockout (AMPKα1 cKO), AMPKα2 conditional knockout (AMPKα2 cKO) and AMPKα1α2 conditional double knockout (AMPKα cDKO) mice, we found that compared with wild-type (WT) littermates, mutant mice displayed accelerated severity of surgically induced OA, especially AMPKα cDKO mice. Furthermore, male but not female AMPKα cDKO mice exhibited severely spontaneous ageing-associated OA lesions at 12 months of age. The chondrocytes isolated from AMPKα cDKO mice resulted in an enhanced interleukin-1β (IL-1β)-stimulated catabolic response. In addition, upregulated expression of matrix metalloproteinase-3 (MMP-3), MMP-13 and phospho-nuclear factor-κB (phospho-NF-κB) p65 and increased levels of apoptotic markers were detected in the cartilage of AMPKα cDKO mice compared with their WT littermates in vivo. Thus, our findings suggest that AMPK activity in chondrocytes is important in maintaining joint homeostasis and OA development.

Highlights

Osteoarthritis (OA) is the most common joint disease and the major cause of disability in aged individuals
Our results indicate that AMPK deficiency in chondrocytes disrupts articular cartilage homeostasis in adults by enhancing catabolic activity and promoting chondrocyte apoptosis in surgery-induced and ageing-associated OA
Apparent decreases in the messenger RNA expression levels of AMPKα1 and AMPKα2 in the articular cartilage of 10-week-old AMPKα cDKO mice were confirmed by q-PCR (n = 6/group; Fig. 1c; Unpaired t-test; AMPKα1, p = 0.005; AMPKα2, p = 0.005)

Summary

Introduction

Osteoarthritis (OA) is the most common joint disease and the major cause of disability in aged individuals. AMPK phosphorylates various downstream substrates, allowing the inhibition of energy (e.g., ATP) consuming cellular processes and the activation of energy-producing processes[4]. In this manner, AMPK is a master regulator of energy homeostasis, and AMPK dysregulation has been implicated in diverse human diseases and ageing[5,6,7]. The accurate effect of AMPK on the maintenance of adult articular cartilage in OA pathogenesis in vivo and its underlying mechanisms were assessed.

Methods

Results

Conclusion