Sirt1 Protects Cartilage Against Degradation through FoxO1 Nucleo-cytoplasmic Shuttling and Positive Regulation of Autophagy

Abstract Background: Sirt1 plays an important role in the pathophysiological process of osteoarthritis (OA) as we reported previously, however, the underlying mechanisms are still poorly addressed. Methods: The cartilage samples from OA patients’ knee joint were collected and detected histologically and immunohistochemistically. The effects of cartilage specific Sirt1 deletion on cartilage homeostasis were evaluated in destabilization of medial meniscus (DMM)-induced OA mice model (n=10). Finally, the underlying regulation of Sirt1 on cartilage was verified by coimmunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) in vitro.Results: The expression levels of SIRT1, FoxO1 and autophagy decreased in OA cartilage. We further found that DMM-induced OA in cartilage specific Sirt1 deletion mice displayed an aggravated OA development, with increased chondrocytes hypertrophy and apoptosis while decreased autophagy activity. In vitro experiments indicated that FoxO1 regulated Sirt1 expression by nucleo-cytoplasmic shuttling through an auto-feedback loop leading to an increased autophagy level. Consistently, the activation of autophagy activity partly rescued OA-like changes in chondrocytes.Conclusions: Sirt1 protects cartilage against degradation through FoxO1 nucleo-cytoplasmic shuttling and positive regulation of autophagy, which all play a protective role in OA pathophysiological process, possibly partial adjustment by positive feedback.