Abstract
Chondrocyte hypertrophy‐like change is an important pathological process of osteoarthritis (OA), but the mechanism remains largely unknown. Neural cell adhesion molecule (NCAM) is highly expressed and involved in the chondrocyte differentiation of mesenchymal stem cells (MSCs). In this study, we found that NCAM deficiency accelerates chondrocyte hypertrophy in articular cartilage and growth plate of OA mice. NCAM deficiency leads to hypertrophic chondrocyte differentiation in both murine MSCs and chondrogenic cells, in which extracellular signal‐regulated kinase (ERK) signaling plays an important role. Moreover, NCAM expression is downregulated in an interleukin‐1β‐stimulated OA cellular model and monosodium iodoacetate‐induced OA rats. Overexpression of NCAM substantially inhibits hypertrophic differentiation in the OA cellular model. In conclusion, NCAM could inhibit hypertrophic chondrocyte differentiation of MSCs by inhibiting ERK signaling and reduce chondrocyte hypertrophy in experimental OA model, suggesting the potential utility of NCAM as a novel therapeutic target for alleviating chondrocyte hypertrophy of OA.
Highlights
Osteoarthritis (OA) is the most common joint disorder worldwide,[1] showing a progressive increase in the last two decades as the leading cause of large social and economic burden.[2,3] The study of OA pathophysiology mainly focuses on the mechanisms of cartilage degeneration and chondrocyte biology.[4]
Chondrocytes mature to two different fates. They either remain as chondrocytes, ceasing differentiation, and forming persistent cartilage located on the surface of the joint, or differentiate into hypertrophic chondrocytes contributing to the mineralization of extracellular matrix (ECM) and formation of the growth plate.[32,33]
We provide the first evidence that Neural cell adhesion molecule (NCAM) plays a novel role in chondrocyte hypertrophy of chondrogenic differentiation
Summary
Osteoarthritis (OA) is the most common joint disorder worldwide,[1] showing a progressive increase in the last two decades as the leading cause of large social and economic burden.[2,3] The study of OA pathophysiology mainly focuses on the mechanisms of cartilage degeneration and chondrocyte biology.[4]. Chondrocyte hypertrophy is an important physiological process involved in the development of long bones from the cartilage anlagen. This stage is marked by increase in cell volume,[8] extracellular matrix (ECM) remodeling, and expression of hypertrophic chondrocyte markers such as type X collagen (Col X), matrix metalloproteinase(MMP)-13, and runt-related transcription factor 2 (RunX2).[9] Chondrocyte hypertrophy was shown to be involved in OA pathogenesis. In the process of chondrogenic differentiation, NCAM is expressed in prechondrogenic cells and increased during cell condensation,[19] but it becomes undetectable in hypertrophic chondrocytes.[20,21] Previous studies showed that NCAM initiated chondrogenesis by promoting and stabilizing the condensation step while may not contribute to chondrocyte differentiation directly.[22,23] the role of NCAM in chondrocyte hypertrophy is still poorly understood. We investigated the underlying signaling pathway in MSCs involved in hypertrophic differentiation of chondrocytes
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