Sustained Akt signaling in articular chondrocytes causes osteoarthritis via oxidative stress-induced senescence in mice

Jing Xie,Qi He,Jingting Lin,Yan Teng,Min Wei,Xiao Yang,Guan Yang

doi:10.1038/s41413-019-0062-y

Abstract

Osteoarthritis (OA) is an age-related disorder that is strongly associated with chondrocyte senescence. The causal link between disruptive PTEN/Akt signaling and chondrocyte senescence and the underlying mechanism are unclear. In this study, we found activated Akt signaling in human OA cartilage as well as in a mouse OA model with surgical destabilization of the medial meniscus. Genetic mouse models mimicking sustained Akt signaling in articular chondrocytes via PTEN deficiency driven by either Col2a1-Cre or Col2a1-CreERT2 developed OA, whereas restriction of Akt signaling reversed the OA phenotypes in PTEN-deficient mice. Mechanistically, prolonged activation of Akt signaling caused an accumulation of reactive oxygen species and triggered chondrocyte senescence as well as a senescence-associated secretory phenotype, whereas chronic administration of the antioxidant N-acetylcysteine suppressed chondrocyte senescence and mitigated OA progression in PTEN-deficient mice. Therefore, inhibition of Akt signaling by PTEN is required for the maintenance of articular cartilage. Disrupted Akt signaling in articular chondrocytes triggers oxidative stress-induced chondrocyte senescence and causes OA.

Highlights

Osteoarthritis (OA) is an age-related disease characterized by articular cartilage degeneration, which is the leading cause of pain and disability worldwide.[1]
We provide in vivo genetic evidence that inhibition of Akt signaling by PTEN is required for the maintenance of articular cartilage, which is achieved through inhibition of oxidative stress-induced chondrocyte senescence
Akt signaling is activated in human OA and experimental OA mouse models We first examined the level of phosphorylated AKT (p-AKT) in human OA cartilage

Summary

INTRODUCTION

Osteoarthritis (OA) is an age-related disease characterized by articular cartilage degeneration, which is the leading cause of pain and disability worldwide.[1]. Excessive reactive oxygen species (ROS) have been demonstrated to be inducers of cellular senescence.[17] In OA chondrocytes, ROS-induced oxidative damage has been implicated as the major cause of cellular senescence, as indicated by reduced capacities for chondrocyte proliferation, survival and extracellular matrix (ECM) synthesis, as well as increased production of matrix-degrading enzymes.[18] Insulin/IGF-1/PI3K/Akt/forkhead-box O (FOXO) signaling is a major pathway that regulates ROS generation and cell senescence.[19,20] FoxO transcriptional factors play a chondroprotective role by supporting oxidative stress resistance.[21,22,23] it remains unknown whether Akt signaling serves as a chondroprotective pathway or executes a prosenescence response during OA pathogenesis in vivo. We provide in vivo genetic evidence that inhibition of Akt signaling by PTEN is required for the maintenance of articular cartilage, which is achieved through inhibition of oxidative stress-induced chondrocyte senescence

RESULTS

DISCUSSION

MATERIALS AND METHODS