Novel Function of Osteocalcin in Chondrocyte Differentiation and Endochondral Ossification Revealed on a CRISPR/Cas9 bglap-bglap2 Deficiency Mouse Model

• Published in: International journal of molecular sciences Vol. 25; no. 18; p. 9945
• Main Authors: Yu, Xiang-Fang, Teng, Bin, Li, Jun-Feng, Zhang, Jian V, Su, Zhe, Ren, Pei-Gen
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.09.2024; MDPI
• Subjects: Animals; Biological research; Biology, Experimental; Bones; Cartilage; Cartilage - metabolism; Cartilage cells; Cell differentiation; Cell Differentiation - genetics; chondrocyte differentiation; Chondrocytes - cytology; Chondrocytes - metabolism; Chondrogenesis - genetics; Collagen; CRISPR; CRISPR-Cas Systems; endochondral ossification; Extracellular matrix; Genes; Growth; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mice; Mice, Knockout; osteocalcin; Osteocalcin - genetics; Osteocalcin - metabolism; Osteogenesis - genetics; Physiological aspects; Protein hormones; Signal Transduction; China; osteocalcin; endochondral ossification; cartilage; chondrocyte differentiation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25189945

Endochondral ossification is the process by which cartilage is mineralized into bone, and is essential for the development of long bones. Osteocalcin (OCN), a protein abundant in bone matrix, also exhibits high expression in chondrocytes, especially hypertrophic chondrocytes, while its role in endochondral ossification remains unclear. Utilizing a new CRISPR/Cas9-mediated deficiency (OCN ) mouse model generated in our laboratory, we provide the first evidence of OCN's regulatory function in chondrocyte differentiation and endochondral ossification. The OCN mice exhibited significant delays in primary and secondary ossification centers compared to wild-type mice, along with increased cartilage length in growth plates and hypertrophic zones during neonatal and adolescent stages. These anomalies indicated that OCN deficiency disturbed endochondral ossification during embryonic and postnatal periods. Mechanism wise, OCN deficiency was found to increase chondrocyte differentiation and postpone vascularization process. Furthermore, bone marrow mesenchymal stromal cells (BMSCs) from OCN mice demonstrated an increased capacity for chondrogenic differentiation. Transcriptional network analysis implicated that BMP and TGF-β signaling pathways were highly affected in OCN BMSCs, which is closely associated with cartilage development and maintenance. This elucidation of OCN's function in chondrocyte differentiation and endochondral ossification contributes to a more comprehensive understanding of its impact on skeletal development and homeostasis.