Lysosomal destabilization: A missing link between pathological calcification and osteoarthritis

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. Pathological calcification becomes progressively more severe as osteoarthritis progresses. The hydroxyapatite crystallites so produced in osteoarthritic cartilage are phagocytized by resident chondrocytes and processed by lysosomes. This results in lysosomal membrane permeabilization and release of cathepsin B. The cytosolic cathepsin B subsequently activates NLRP3 inflammasomes which, in turn, trigger chondrocyte pyroptosis and IL-1β release. These processes ultimately result in deterioration of the osteoarthritic cartilage. Alleviating lysosomal membrane permeabilization and release of cathepsin B by CA074me retards the progression of osteoarthritis. [Display omitted] •Cartilage calcification by hydroxyapatite becomes progressively more severe as osteoarthritis progresses.•Hydroxyapatite engulfed by chondrocytes triggers lysosomal membrane permeabilization and cytosolic release of cathepsin B.•The cytosolic cathepsin B instigates NLRP3 inflammasome activation and chondrocyte pyroptosis to deteriorate cartilage.•Alleviating lysosomal destabilization prevents the progression of osteoarthritis.