期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 48, 页码 30488-30497出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2017056117
关键词
TGFb; FoxO1; osteoarthritis; articular chondrocyte; autophagy
资金
- NIH Grant: R01 grant [AR075860, AR077616, AR069605]
- NIH Grant: R21 grant [AR077226]
- NIH Grant: T32 training grant [AR060719]
- NIH Grant: P30 Core Center Grant [AR057235]
Transforming growth factor-beta (TGF-beta) signaling is a critical regulator for articular cartilage tissue maintenance and chondrocyte homeostasis. Nonetheless, the regulatory networks and downstream signaling pathways that govern the chondroprotective function of TGF-beta in the context of osteoarthritis (OA) are not fully defined. Recent studies reveal that mice with postnatal deletion of triple forkhead box class Os (FoxOs) (1, 3, and 4) spontaneously develop OA-like pathologies. The OA phenotype largely recapitulates that observed in mice with loss of TGF-beta R2. In the present study, we investigated the role of FoxOs as downstream mediators of TGF-beta signaling and define their role in articular cartilage homeostasis. Among the three FoxOs (1, 3, and 4), TGF-beta signaling exclusively regulates FoxO1 in a TGF-beta activated kinase 1 (TAK1)-dependent manner. Furthermore, FoxO1 was genetically ablated in mice in a tissue-specific manner in articular cartilage or overexpressed in adult cartilage immediately followed by meniscal/ligament injury (MLI). Histological and microcomputed tomography (micro-CT) analyses demonstrated that loss of FoxO1 postnatally in articular cartilage leads to OA-like pathologies, and gain of FoxO1 in adult cartilage has both preventative and therapeutic effects on surgically induced OA. Mechanistically, FoxO1 was found to maintain articular chondrocyte homeostasis through induction of anabolic and autophagy-related gene expressions. Importantly, overexpression of FoxO1 markedly rescued the OA phenotypes caused by deficiency in TGF-beta signaling in chondrocytes. Our study identifies that TGF-beta/TAK1-FoxO1 is a key signaling cascade in regulation of articular cartilage autophagy and homeostasis and is a potentially important therapeutic target for OA-like joint diseases.
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