Sirt3 Promotes Chondrogenesis, Chondrocyte Mitochondrial Respiration and the Development of High-Fat Diet-Induced Osteoarthritis in Mice

Abstract

Understanding how obesity‐induced metabolic stress contributes to synovial joint tissue damage is difficult because of the complex role of metabolism in joint development, maintenance, and repair. Chondrocyte mitochondrial dysfunction is implicated in osteoarthritis (OA) pathology, which motivated us to study the mitochondrial deacetylase enzyme sirtuin 3 (Sirt3). We hypothesized that combining high‐fat‐diet (HFD)‐induced obesity and cartilage Sirt3 loss at a young age would impair chondrocyte mitochondrial function, leading to cellular stress and accelerated OA. Instead, we unexpectedly found that depleting cartilage Sirt3 at 5 weeks of age using Sirt3‐flox and Acan‐CreERT2 mice protected against the development of cartilage degeneration and synovial hyperplasia following 20 weeks of HFD. This protection was associated with increased cartilage glycolysis proteins and reduced mitochondrial fatty acid metabolism proteins. Seahorse‐based assays supported a mitochondrial‐to‐glycolytic shift in chondrocyte metabolism with Sirt3 deletion. Additional studies with primary murine juvenile chondrocytes under hypoxic and inflammatory conditions showed an increased expression of hypoxia‐inducible factor (HIF‐1) target genes with Sirt3 deletion. However, Sirt3 deletion impaired chondrogenesis using a murine bone marrow stem/stromal cell pellet model, suggesting a context‐dependent role of Sirt3 in cartilage homeostasis. Overall, our data indicate that Sirt3 coordinates HFD‐induced changes in mature chondrocyte metabolism that promote OA. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3‐COX4I2 Axis Attenuates Osteoarthritis Progression

“…However, a most recent work by Zhu et al reported that cartilage-specific deletion of SIRT3 ameliorates cartilage degeneration and synovial hyperplasia in high-fat diet (HFD)-induced metabolic OA model. [43] The enhanced glycolysis and suppressed mitochondrial fatty acid metabolism induced by SIRT3 loss may serve as the leading causes. Differing from other cell types, owing to the avascular structure, in vivo, chondrocytes produce energy mainly though anaerobic respiration.…”

Sirtuins in osteoarthritis: current understanding

“…SIRT3 regulates mitochondrial functions and maintains redox homeostasis to prevent oxidative stress via its deacetylation activity in chondrocyte (36). Seahorse-based assays supported a mitochondrial-to-glycolytic shift in chondrocyte metabolism after SIRT3 deletion, resulting in energy shortage, which indicated that SIRT3 is crucial for mitochondrial respiration (37). In addition, Chen et al reported that AMPK and SIRT3 can regulate each other, and their expression and activity are always consistent in chondrocytes, which suggests the existence of an AMPK-SIRT3 positive feedback loop (38).…”

“…SIRT3 regulates mitochondrial functions and maintains redox homeostasis to prevent oxidative stress via its deacetylation activity in chondrocyte ( 36 ). Seahorse-based assays supported a mitochondrial-to-glycolytic shift in chondrocyte metabolism after SIRT3 deletion, resulting in energy shortage, which indicated that SIRT3 is crucial for mitochondrial respiration ( 37 ). In addition, Chen et al.…”

Epigenetics as a Therapeutic Target in Osteoarthritis

“…Moreover, it enhances mitochondrial respiration and fatty acid metabolism, thereby promoting HFD-induced OA. However, the deletion of Sirt3 plays a detrimental role in chondrogenesis when using a murine bone marrow stem cell pellet model, so its role on cartilage homeostasis has yet to be fully elucidated [ 93 ].…”