Du Zhangzhen, Zhao Yongqi, Zhang Ke, Qin Qiaozhen, Luo Changyi, Wu Jiamei, Zhang Heyang, Liu Shuirong, Xu Zhenhua, Zheng Jing, Fan Shuli, Jiang Xiaoxia, Li Xu, Wang Yan
Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P.R. China.
The First Hospital of China Medical University, Shenyang 110000, P.R. China.
Int J Biol Sci. 2025 Jun 23;21(10):4353-4373. doi: 10.7150/ijbs.105560. eCollection 2025.
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.
初步研究确定骨钙素（OCN）是骨形成的关键因素。完全羧化的骨钙素（cOCN）对骨基质中的羟基磷灰石具有高亲和力，但在特定生理条件下，它可能会发生脱羧反应，从而获得内分泌调节能力。最近的研究结果表明，羧化不足的骨钙素（ucOCN）在骨骼之外可能具有潜在的保护作用，影响包括大脑、胰腺、肌肉和性腺在内的各种系统，其作用已得到充分证实。虽然细胞内OCN表达增加通常被认为是骨关节炎（OA）和软骨细胞肥大的标志物，但细胞外ucOCN在软骨细胞中的具体作用在很大程度上仍未被探索，也很少受到关注，尤其是其调节OA相关变化的潜力。本研究使用OCN基因敲除（OCN）小鼠，发现缺乏OCN会增加软骨细胞中X型胶原蛋白（COL10）和基质金属蛋白酶13（MMP13）的表达，尽管没有严重的OA表型。在关节炎模型和OA患者中观察到滑液中ucOCN呈下降趋势，提示其在OA进展中发挥作用。在小鼠关节炎模型中，ucOCN水平升高导致COL10a1和MMP13表达下调，同时软骨完整性显著改善。此外，ucOCN调节G蛋白偶联受体C类第6组成员A（GPRC6A）和缺氧诱导因子1α（HIF-1α）信号通路，促进软骨细胞中TIMP3表达和自噬，表明其保护作用背后存在独特的分子机制。
