Undercarboxylated OCN Inhibits Chondrocyte Hypertrophy and Osteoarthritis Development through GPRC6A/HIF-1α Cascade.

Abstract

Initial investigations established osteocalcin (OCN) as a pivotal factor in bone formation. Fully carboxylated osteocalcin (cOCN) exhibits a high affinity for hydroxyapatite within the bone matrix, yet under specific physiological conditions, it may undergo decarboxylation, thereby acquiring endocrine regulatory capabilities. Recent findings suggest a potential protective role for undercarboxylated osteocalcin (ucOCN) beyond bone, influencing various systems, including the brain, pancreas, muscle, and gonads, where its effects are well established. Although increased intracellular OCN expression is often considered a marker of osteoarthritis (OA) and chondrocyte hypertrophy, the specific role of extracellular ucOCN in chondrocytes remains largely unexplored and has received little attention, especially regarding its potential to modulate OA-related changes. This study used OCN knockout (OCN^-/-) mice and found that OCN absence increased collagen type X (COL10) and matrix metalloproteinase 13 (MMP13) expression in chondrocytes, despite a lack of severe OA phenotype. A declining trend of ucOCN in synovial fluid was observed in arthritis models and OA patients, suggesting a role in OA progression. Elevation of ucOCN levels led to the downregulation of COL10a1 and MMP13 expression, accompanied by a marked improvement in cartilage integrity in murine models of arthritis. Additionally, ucOCN regulated the G protein-coupled receptor class C group 6 member A (GPRC6 A) and Hypoxia-inducible factor 1-alpha (HIF-1α) pathways, promoting TIMP3 expression and autophagy in chondrocytes, indicating distinct molecular mechanisms behind its protective effects.