Bglap and Bglap2, encoding osteocalcin (OCN), are genes crucial for skeletal development. OCN, the most abundant non-collagenous protein in the bone matrix, is involved in regulating the alignment of apatite crystals parallel to collagen fibers [1,2,5,6,8]. These genes are part of the bone development pathway, with their expression regulated by transcription factors like Runx2 in osteoblasts [1,2,5,7]. Genetic models, such as knockout mice, are valuable for studying their functions.

In KO mouse models, deletion of Bglap and Bglap2 (OCN-deficient mice) shows that OCN is not involved in regulating glucose metabolism, testosterone synthesis, or muscle mass, contrary to previous claims [4,8]. However, it is essential for endochondral ossification. OCN-deficient mice exhibit delays in primary and secondary ossification centers, increased cartilage length in growth plates, and disturbed chondrocyte differentiation and vascularization [3]. Also, the alignment of hydroxyapatite crystals and collagen fibers is significantly impaired in triple-gene (including Bglap3) knockout mice, leading to changes in bone quality under simulated bone-loss conditions [6].

In conclusion, Bglap and Bglap2 are vital for skeletal development, specifically in processes like endochondral ossification and maintaining the alignment of bone minerals and collagen fibers. The study of Bglap&Bglap2 KO mouse models has clarified that OCN does not function as a hormone regulating glucose metabolism, testosterone synthesis, or muscle mass. These models contribute to understanding the mechanisms of skeletal development and bone-related diseases, providing insights into potential therapeutic targets for bone disorders [3,4,6,8].

References:

1. Komori, Toshihisa. 2022. Whole Aspect of Runx2 Functions in Skeletal Development. In International journal of molecular sciences, 23, . doi:10.3390/ijms23105776. https://pubmed.ncbi.nlm.nih.gov/35628587/

2. Komori, Toshihisa. 2024. Regulation of Skeletal Development and Maintenance by Runx2 and Sp7. In International journal of molecular sciences, 25, . doi:10.3390/ijms251810102. https://pubmed.ncbi.nlm.nih.gov/39337587/

3. Yu, Xiang-Fang, Teng, Bin, Li, Jun-Feng, Su, Zhe, Ren, Pei-Gen. 2024. Novel Function of Osteocalcin in Chondrocyte Differentiation and Endochondral Ossification Revealed on a CRISPR/Cas9 bglap-bglap2 Deficiency Mouse Model. In International journal of molecular sciences, 25, . doi:10.3390/ijms25189945. https://pubmed.ncbi.nlm.nih.gov/39337434/

4. Diegel, Cassandra R, Hann, Steven, Ayturk, Ugur M, Warman, Matthew L, Williams, Bart O. 2020. An osteocalcin-deficient mouse strain without endocrine abnormalities. In PLoS genetics, 16, e1008361. doi:10.1371/journal.pgen.1008361. https://pubmed.ncbi.nlm.nih.gov/32463812/

5. Komori, Toshihisa. 2024. Bone development by Hedgehog and Wnt signaling, Runx2, and Sp7. In Journal of bone and mineral metabolism, 43, 33-38. doi:10.1007/s00774-024-01551-1. https://pubmed.ncbi.nlm.nih.gov/39352550/

6. Xu, Zihan, Yang, Chao, Wu, Feng, Dai, Zhongquan, Li, Yinghui. 2023. Triple-gene deletion for osteocalcin significantly impairs the alignment of hydroxyapatite crystals and collagen in mice. In Frontiers in physiology, 14, 1136561. doi:10.3389/fphys.2023.1136561. https://pubmed.ncbi.nlm.nih.gov/37057181/

7. Qin, Xin, Jiang, Qing, Komori, Hisato, Miyazaki, Toshihiro, Komori, Toshihisa. 2021. Runt-related transcription factor-2 (Runx2) is required for bone matrix protein gene expression in committed osteoblasts in mice. In Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 36, 2081-2095. doi:10.1002/jbmr.4386. https://pubmed.ncbi.nlm.nih.gov/34101902/

8. Moriishi, Takeshi, Ozasa, Ryosuke, Ishimoto, Takuya, Amizuka, Norio, Komori, Toshihisa. 2020. Osteocalcin is necessary for the alignment of apatite crystallites, but not glucose metabolism, testosterone synthesis, or muscle mass. In PLoS genetics, 16, e1008586. doi:10.1371/journal.pgen.1008586. https://pubmed.ncbi.nlm.nih.gov/32463816/