Autophagy attenuates osteoarthritis in mice by inhibiting chondrocyte pyroptosis and improving subchondral bone remodeling
Keywords:Osteoarthritis, chondrocyte, autophagy, pyroptosis, subchondral bone
Osteoarthritis (OA) is an age-related degenerative disease characterized by cartilage degeneration and abnormal bone remodeling in the subchondral bone. Autophagy maintains cellular homeostasis by self-phagocytosis. However, the underlying mechanisms of autophagy on the pathological progression of OA are still unknown. This study assessed the effects of autophagy on cartilage and subchondral bone in a mouse OA model. A mouse OA model was induced using destabilization of the medial meniscus (DMM) surgery. Assessment was performed by histomorphology, microcomputed tomography (micro-CT), immunohistochemical, immunofluorescent, and tartrate-resistant acid phosphatase (TRAP) staining. Our data revealed that autophagy can significantly delay the pathological progression of OA by increasing the thickness of hyaline cartilage and decreasing the thickness of calcified cartilage, increasing the subchondral bone volume fraction and bone mineralization density, and decreasing trabecular separation in the early stages of OA (2 weeks), whereas the opposite is true in the late stages of OA (8 weeks). Mechanistically, activation of autophagy in cartilage increased the expression of type II collagen (Col II), decreased the expression of matrix metalloproteinase 13 (MMP 13) and decreased the pyroptosis mediated by NOD-like receptor protein 3 (NLRP3) inflammasome by decreasing the expression of NLRP3, caspase-1, gasdermin D (GSDMD), and IL-1β. In the subchondral bone, activation of autophagy decreased the generation of mature osteoclasts at the early stages of OA (2 weeks) mainly by reducing the receptor activator for nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio, while it decreased osteoblastogenesis by reducing Runt-related transcription factor 2 (Runx2) expression significantly in the late stages of OA (8 weeks). In conclusion, autophagy may delay the pathological progression of OA in mice by inhibiting chondrocyte pyroptosis and improving subchondral bone remodeling.
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Copyright (c) 2022 Jiangbo Yan, Gangning Feng, Yong Yang, Dong Ding, Long Ma, Xin Zhao, Xiaolei Chen, Hui Wang, Zhirong Chen, Qunhua Jin
This work is licensed under a Creative Commons Attribution 4.0 International License.