Aloe-emodin alleviates osteoarthritis and maintains cytoskeletal homeostasis via targeting Septin7 ubiquitination.
Osteoarthritis (OA) is the leading cause of disability worldwide. Due to its complex pathogenesis, no disease-modifying therapies currently exist to halt its progression. Consequently, there is an urgent clinical need to develop effective pharmacological interventions that attenuate cartilage damage and treat OA.
This study aimed to evaluate the therapeutic effects of Aloe-emodin (AE) in experimental models of OA and to investigate whether AE regulates chondrocyte cytoskeletal organization via Septin7-associated mechanisms.
A destabilization of the medial meniscus (DMM) rat model was established to evaluate the impact of AE on joint pathology and cartilage integrity. Concurrently, primary rat chondrocytes were stimulated with interleukin-1β (IL-1β) to establish an in vitro model of OA-like degeneration. Transcriptomic screening, biochemical assays, and molecular analyses were performed to identify AE-interacting targets and to examine cytoskeletal organization, ubiquitination-related mechanisms, and associated signaling pathways.
AE interacts with key amino acid residues (Ser59 and Asp119) of Septin7, promotes RNF20 binding to Septin7, and accelerates its ubiquitin-proteasome-mediated degradation. This targeted degradation suppresses GTP-RhoA activation and its downstream signaling cascades, including the ROCK/Cofilin and FAK/Src pathways, thereby achieving precise regulation of chondrocyte cytoskeletal remodeling and metabolic homeostasis. Notably, Septin7 expression is significantly elevated in both serum and macroscopically intact and highly degenerated cartilage tissue from OA patients, highlighting its dual potential as a biomarker and a therapeutic target. Furthermore, intra-articular injection of an adenovirus to silence Septin7 attenuated DMM-induced joint structural damage in vivo.
Our findings demonstrate that Septin7 serves as both a therapeutic target and a serum biomarker for OA. Furthermore, the natural compound AE effectively delays OA progression by restoring chondrocyte cytoskeletal homeostasis and promoting the degradation of Septin7 via the RNF20-mediated ubiquitin-dependent degradation pathway.
This study aimed to evaluate the therapeutic effects of Aloe-emodin (AE) in experimental models of OA and to investigate whether AE regulates chondrocyte cytoskeletal organization via Septin7-associated mechanisms.
A destabilization of the medial meniscus (DMM) rat model was established to evaluate the impact of AE on joint pathology and cartilage integrity. Concurrently, primary rat chondrocytes were stimulated with interleukin-1β (IL-1β) to establish an in vitro model of OA-like degeneration. Transcriptomic screening, biochemical assays, and molecular analyses were performed to identify AE-interacting targets and to examine cytoskeletal organization, ubiquitination-related mechanisms, and associated signaling pathways.
AE interacts with key amino acid residues (Ser59 and Asp119) of Septin7, promotes RNF20 binding to Septin7, and accelerates its ubiquitin-proteasome-mediated degradation. This targeted degradation suppresses GTP-RhoA activation and its downstream signaling cascades, including the ROCK/Cofilin and FAK/Src pathways, thereby achieving precise regulation of chondrocyte cytoskeletal remodeling and metabolic homeostasis. Notably, Septin7 expression is significantly elevated in both serum and macroscopically intact and highly degenerated cartilage tissue from OA patients, highlighting its dual potential as a biomarker and a therapeutic target. Furthermore, intra-articular injection of an adenovirus to silence Septin7 attenuated DMM-induced joint structural damage in vivo.
Our findings demonstrate that Septin7 serves as both a therapeutic target and a serum biomarker for OA. Furthermore, the natural compound AE effectively delays OA progression by restoring chondrocyte cytoskeletal homeostasis and promoting the degradation of Septin7 via the RNF20-mediated ubiquitin-dependent degradation pathway.
Authors
Li Li, Chen Chen, Zhang Zhang, Cheng Cheng, Wang Wang, Li Li, Du Du, Duan Duan, Liao Liao, Wang Wang, Zhang Zhang, Wang Wang, Lv Lv, He He, Zhang Zhang, Ji Ji, Li Li, Yuan Yuan, Du Du, Yang Yang
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