Autophagy attenuates osteoarthritis in mice by inhibiting chondrocyte pyroptosis and improving subchondral bone remodeling

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 surgery. Assessment was performed by histomorphology, microcomputed tomography, immunohistochemical, immunofluorescent, and tartrate-resistant acid phosphatase 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 (two weeks), whereas the opposite is true in the late stages of OA (eight weeks). Mechanistically, activation of autophagy in cartilage increased the expression of type II collagen, decreased the expression of matrix metalloproteinase 13, and decreased the pyroptosis mediated by NOD-like receptor protein 3 inflammasome by decreasing the expression of NOD-like receptor protein 3 inflammasome, caspase-1, gasdermin D, and interleukin-1β. In the subchondral bone, activation of autophagy decreased the generation of mature osteoclasts at the early stages of OA (two weeks) mainly by reducing the receptor activator for nuclear factor-κB ligand/osteoprotegerin ratio, while it decreased osteoblastogenesis by reducing Runt-related transcription factor 2 expression significantly in the late stages of OA (eight weeks). In conclusion, autophagy may delay the pathological progression of OA in mice by inhibiting chondrocyte pyroptosis and improving subchondral bone remodeling.