Open AccessFoxO1 is a crucial mediator of TGF-β/TAK1 signaling and protects against osteoarthritis by maintaining articular cartilage homeostasis
Author(s) -
Cuicui Wang,
Jie Shen,
Jun Ying,
Dengpan Xiao,
Regis J. O’Keefe
Publication year - 2020
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2017056117
Subject(s) - osteoarthritis , mediator , foxo1 , cartilage , articular cartilage , medicine , homeostasis , transforming growth factor , transforming growth factor beta , signal transduction , bioinformatics , cancer research , microbiology and biotechnology , biology , pathology , anatomy , protein kinase b , alternative medicine
Transforming growth factor-β (TGF-β) 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-β 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-βR2. In the present study, we investigated the role of FoxOs as downstream mediators of TGF-β signaling and define their role in articular cartilage homeostasis. Among the three FoxOs (1, 3, and 4), TGF-β signaling exclusively regulates FoxO1 in a TGF-β 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-β signaling in chondrocytes. Our study identifies that TGF-β/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.