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

Abstract

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.

Flavokawain A alleviates the progression of mouse osteoarthritis: An in vitro and in vivo study

“…Numerous pieces of evidence indicate that a crucial role is played by autophagy in the progression of OA ( Musumeci et al, 2015 ; Liu et al, 2021 ; Yan et al, 2022 ). Therefore, we analyzed the impacts of FKA on autophagy in IL-1β-treated mouse chondrocyte cells.…”

General Control Non-derepressible 2 Alleviates Cartilage Degeneration and Inhibits NLRP3 Inflammasome Activation in Osteoarthritis

“…25 Autophagy, a protective mechanism of cells, is reported to participate in a variety of biological functions such as cell differentiation, cell proliferation, and apoptosis. 26,27 Yan et al 28 have proved that autophagy can attenuate OA in mice by suppressing chondrocyte pyroptosis and improving subchondral bone remodeling. Moreover, a study by Bay-Jensen et al 29 has confirmed that maintaining autophagy level in chondrocytes In recent years, increasing researchers have focused on the vital functions of NLRP3 inflammasome in immune-associated diseases, including OA.…”

Pyroptosis and degenerative diseases of the elderly

“…At the level of gene expression, miR-107 [ 125 ], miR-140-5p, miR-155, miR-219a-5p [ 126 ], and miR-326 [ 127 ] can inhibit chondrocyte pyroptosis, potentially providing a new therapeutic modality. Preclinical studies have demonstrated that icariin [ 128 ], loganin [ 129 ], licochalcone Am [ 130 ], irisin [ 131 ], quercetin [ 126 ], morroniside [ 132 ], and rapamycin [ 133 ] inhibit the classical pyroptotic pathway and reduce chondrocyte death, suggesting future roles in the treatment of OA. In addition, combined treatment with antagonists of GSDMD (disulfiram) and HMGB1 (glycyrrhizic acid) can attenuate chondrocyte pyroptosis, inhibit inflammation, and promote chondrocyte proliferation in vitro, thereby suggesting a therapeutic approach for OA [ 134 ].…”