Temporal-spatial progress of cartilage nanocalcification in osteoarthritis development

Abstract While osteoarthritis (OA) involves pathological cartilage calcification, its progress is not fully understood. Here, we investigated the temporal-spatial mechanism of mineral transformation pathways in human OA cartilage tissues via multiple imaging tomography at nanoscale resolution. We found that OA progressed by both top-down calcification at the joint surface and bottom-up calcification at the osteochondral transition zone. The top-down calcification process started with the formation of spherical mineral particles in the joint surface during early-stage OA (OA-E), followed by fiber formation and compact material transformation deep into the cartilage during advanced-stage OA (OA-A). The bottom-up calcification in OA-E started when an excessive layer of calcified tissue formed above the original calcified cartilage; there was a 100–200 µm thick layer of noncalcified cartilage tissues between the original and new calcified layers, forming a sandwich structure at the osteochondral transition zone. The abnormal calcified layer was located at the edge of the tidemark that contained acidic components (-COOH) that can chelate Ca2+ and bind with PO43− to form crystals. It is likely that this local mineralization process was assisted by nearby hypertrophic chondrocytes. With OA progression, the original and upper layers of calcified cartilage fused, which thickened the calcified cartilage region and disrupted cartilage. During OA-E, the calcified cartilage was hypermineralized and contained stiffer carbonated hydroxyapatite (Hap); during OA-A, it was hypomineralized and contained softer HAp. Distinct mechanisms, such as nucleation on matrix vesicles in OA-E and carbonate cores in OA-A, may be involved. These findings illustrated that the progress of pathological calcification was location-specific at the joint surface and osteochondral interface in the early and advanced stages of OA. It is very important to understand the mechanism of OA progression and develop better strategies for future OA treatment on targeting cartilage pathological calcification