Calcification of cartilage by hydroxyapatite is a hallmark of osteoarthritis and its deposition strongly correlates with the severity of osteoarthritis.However,no effective strategies are available to date on the prev...Calcification of cartilage by hydroxyapatite is a hallmark of osteoarthritis and its deposition strongly correlates with the severity of osteoarthritis.However,no effective strategies are available to date on the prevention of hydroxyapatite deposition within the osteoarthritic cartilage and its role in the pathogenesis of this degenerative condition is still controversial.Therefore,the present work aims at uncovering the pathogenic mechanism of intra-cartilaginous hydroxyapatite in osteoarthritis and developing feasible strategies to counter its detrimental effects.With the use of in vitro and in vivo models of osteoarthritis,hydroxyapatite crystallites deposited in the cartilage are found to be phagocytized by resident chondrocytes and processed by the lysosomes of those cells.This results in lysosomal membrane permeabilization(LMP)and release of cathepsin B(CTSB)into the cytosol.The cytosolic CTSB,in turn,activates NOD-like receptor protein-3(NLRP3)inflammasomes and subsequently instigates chondrocyte pyroptosis.Inhibition of LMP and CTSB in vivo are effective in managing the progression of osteoarthritis.The present work provides a conceptual therapeutic solution for the prevention of osteoarthritis via alleviation of lysosomal destabilization.展开更多
基金supported by National Natural Science Foundation of China(82001072,81870805,82170978)National Key R&D Program of China(2022YFC2405900,2022YFC2405901)the Shaanxi Key Scientific and Technological Innovation Team(2020TD-033).
文摘Calcification of cartilage by hydroxyapatite is a hallmark of osteoarthritis and its deposition strongly correlates with the severity of osteoarthritis.However,no effective strategies are available to date on the prevention of hydroxyapatite deposition within the osteoarthritic cartilage and its role in the pathogenesis of this degenerative condition is still controversial.Therefore,the present work aims at uncovering the pathogenic mechanism of intra-cartilaginous hydroxyapatite in osteoarthritis and developing feasible strategies to counter its detrimental effects.With the use of in vitro and in vivo models of osteoarthritis,hydroxyapatite crystallites deposited in the cartilage are found to be phagocytized by resident chondrocytes and processed by the lysosomes of those cells.This results in lysosomal membrane permeabilization(LMP)and release of cathepsin B(CTSB)into the cytosol.The cytosolic CTSB,in turn,activates NOD-like receptor protein-3(NLRP3)inflammasomes and subsequently instigates chondrocyte pyroptosis.Inhibition of LMP and CTSB in vivo are effective in managing the progression of osteoarthritis.The present work provides a conceptual therapeutic solution for the prevention of osteoarthritis via alleviation of lysosomal destabilization.
