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

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Cell Differentiation*/genetics ; Chondrocytes*/metabolism ; Chondrocytes*/cytology ; Chondrogenesis*/genetics ; CRISPR-Cas Systems* ; Osteocalcin*/metabolism ; Osteocalcin*/genetics ; Osteogenesis*/genetics; Animals ; Mice ; Cartilage/metabolism ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cells/cytology ; Mice, Knockout ; Signal Transduction
    • Abstract:
      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 bglap-bglap2 deficiency (OCN em ) mouse model generated in our laboratory, we provide the first evidence of OCN's regulatory function in chondrocyte differentiation and endochondral ossification. The OCN em 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 em mice demonstrated an increased capacity for chondrogenic differentiation. Transcriptional network analysis implicated that BMP and TGF-β signaling pathways were highly affected in OCN em 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.
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    • Grant Information:
      2021YFA0719303 National Key R&D Program of China; 32100572 National Natural Science Foundation of China; 32271166 National Natural Science Foundation of China; 2024A1515013017 Guangdong Basic and Applied Basic Research Foundation; JCYJ20200109115441918 Shenzhen Science and Technology Program; JCYJ20210324102013035 Shenzhen Science and Technology Program; SZGSP012 High-level Key Clinical Specialty project of Guangdong Provincial Health Commission (Supporting construction funds of Shenzhen); LCYJ2022071 Guangdong High-level Hospital Construction Fund and Guangdong High-level Hospital Construction Fund Clinical Research Project of Shenzhen Children's Hospital
    • Contributed Indexing:
      Keywords: cartilage; chondrocyte differentiation; endochondral ossification; osteocalcin
    • Accession Number:
      104982-03-8 (Osteocalcin)
    • Publication Date:
      Date Created: 20240928 Date Completed: 20240928 Latest Revision: 20241007
    • Publication Date:
      20241007
    • Accession Number:
      PMC11431882
    • Accession Number:
      10.3390/ijms25189945
    • Accession Number:
      39337434