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Gene Review

Bglap2  -  bone gamma-carboxyglutamate protein 2

Mus musculus

Synonyms: BGP2, Bglap1, Bgp, OG2, Og2, ...
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Disease relevance of Bglap2

  • Histomorphometric studies done before and after ovariectomy showed that the absence of osteocalcin leads to an increase in bone formation without impairing bone resorption [1].
  • While osteocalcin-deficient mice have increased bone formation, MGP-deficient mice have abnormal calcification leading to osteopenia, fractures, and premature death owing to arterial calcification [2].
  • Osteocalcin promoter-based toxic gene therapy for the treatment of osteosarcoma in experimental models [3].
  • The runt domain site is identical to an osteoblast-specific element-2 or acute myelogenous leukemia binding sequence in the mouse and rat osteocalcin genes, respectively [4].
  • RESULTS: GH tg mice displayed a significant increase in body weight (up to 50%) and BMC (up to 90%), but serum osteocalcin was significantly reduced compared with controls [5].

High impact information on Bglap2


Chemical compound and disease context of Bglap2

  • Surprisingly, serum osteocalcin levels, a biochemical marker of bone formation, suggested that the bone-sparing effects of IL-7 neutralization were due not only to inhibition of bone resorption, but also to stimulation of bone formation [10].
  • Osteosarcoma tumor growth was inhibited more efficiently than by either Ad-OC-TK plus ACV (P < 0.05) or MTX treatment (P < 0.005) alone [11].
  • Chemogene therapy: osteocalcin promoter-based suicide gene therapy in combination with methotrexate in a murine osteosarcoma model [11].
  • The discovery of OC expression in prostate cancer specimens led us to study the regulation of OC gene in androgen-independent metastatic human prostate PC3 cells [12].
  • This relatively rapid change was associated with an increase in plasma osteocalcin, a marker of bone formation, while a decrease in bone resorption reflected by a decrease in urinary hydroxyproline excretion was observed in parallel [13].

Biological context of Bglap2

  • From sequence inspection, DNA transfection experiments, and DNA binding assays, we could not identify a functional vitamin D-responsive element in the promoter of OG2 or in the first 3.3 kilobases of the OG1 promoter [14].
  • Furthermore, during embryogenesis, OG1 and OG2 begin to be expressed at day 15.5, while ORG is transcribed as early as day 10 [15].
  • We examine Osc expression by in situ hybridization during murine development, detailing temporospatial relationships with Msx2 expression during preappositional and appositional odontogenesis and calvarial osteogenesis [16].
  • Northern blot analysis revealed that in the Ad/PDGF-A treated implants OPN was increased, whereas OC gene expression was downregulated at 3 weeks [17].
  • On the other hand, Ad/PDGF-1308 inhibited mineralization of tissue-engineered cementum possibly due to the observed downregulation of BSP and OC and a persistence of stimulation of MNGCs [17].

Anatomical context of Bglap2


Associations of Bglap2 with chemical compounds

  • Consistent with these DNA binding data, a mutation in OSE2 in the OG2 promoter abrogated the inhibitory effect of 1,25-(OH)2D3 treatment on this promoter activity [14].
  • Osteocalcin and osteopontin are noncollagenous proteins secreted by osteoblasts and regulated by a complex interplay of systemic and locally produced factors, including growth factors and steroid hormones [22].
  • Menaquinone-7 regulates the expressions of osteocalcin, OPG, RANKL and RANK in osteoblastic MC3T3E1 cells [23].
  • Here, we examined the mRNA expressions of OPN, MGP, ON, and OC in the kidneys of stone-forming model rats administered an oxalate precursor, ethylene glycol (EG) for up to 28 days [24].
  • However, when cells were treated acutely with 1,25(OH)2D3 at later times during growth in ascorbic acid, the induction of mouse osteocalcin protein was only partially inhibited [25].

Regulatory relationships of Bglap2

  • Overexpression of wild-type PTH-1R increased cell numbers and promoted osteocalcin gene expression versus inactivated mutant receptors [26].
  • This member of the runt/Cbfa family of transcription factors was first identified as the nuclear protein binding to an osteoblast-specific cis-acting element activating the expression of Osteocalcin, the most osteoblast-specific gene [27].
  • Therefore, KCA-098 had a bidirectional effect on the differentiation of osteoblasts (i.e., stimulating both alkaline phosphatase activity and synthesis of CDP and inhibiting osteocalcin synthesis) [28].

Other interactions of Bglap2

  • We named them osteocalcin gene 1 (OG1), osteocalcin gene 2 (OG2), and osteocalcin-related gene (ORG) in order from the 5' end to the 3' end of the cluster [15].
  • Collectively, these studies establish that actions of PTH on the osteocalcin gene are mediated by multiple signaling pathways and require OSE1 and associated nuclear proteins [21].
  • Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts [29].
  • Incubating primary muscle cells with 300 ng/ml of BMP-2 for 6 d also inhibited myotube formation, whereas induced ALP activity and osteocalcin production [30].
  • OG2 Phex transgenic Hyp mice did exhibit a small, but significant, increase in bone mineral density and dry ashed weight, suggesting a partial mineralization effect from restoration of Phex function in mature osteoblasts [31].

Analytical, diagnostic and therapeutic context of Bglap2

  • The mRNA expression of alkaline phosphatase and osteocalcin was increased by SFs from patients with OA, whereas only osteocalcin mRNA was increased by SFs from patients with a loose prosthesis [32].
  • Here we show that OSE1 is a cis-acting element as important as OSE2 for the osteoblast-specific expression of OG2 in cell culture and transgenic mice [33].
  • Southern blot analysis and restriction mapping of genomic DNA from several strains of mice indicated the presence of at least three copies of the OC coding sequence within a 19 kb fragment [34].
  • Finally, chromatin immunoprecipitation analysis in MC3T3-E1 cells showed in vivo occupancy of the OG2 promoter by Runx2 and C/EBPdelta [35].
  • Our results revealed that reduced Nurr1 expression, using Nurr1 siRNA in MC3T3-E1 cells, affected the expression of osteoblast differentiation marker genes, osteocalcin (OCN) and collagen type I alpha 1 (COL1A1), as measured by quantitative real-time PCR [36].


  1. Increased bone formation in osteocalcin-deficient mice. Ducy, P., Desbois, C., Boyce, B., Pinero, G., Story, B., Dunstan, C., Smith, E., Bonadio, J., Goldstein, S., Gundberg, C., Bradley, A., Karsenty, G. Nature (1996) [Pubmed]
  2. Skeletal functions of vitamin K-dependent proteins: not just for clotting anymore. Booth, S.L. Nutr. Rev. (1997) [Pubmed]
  3. Osteocalcin promoter-based toxic gene therapy for the treatment of osteosarcoma in experimental models. Ko, S.C., Cheon, J., Kao, C., Gotoh, A., Shirakawa, T., Sikes, R.A., Karsenty, G., Chung, L.W. Cancer Res. (1996) [Pubmed]
  4. Parathyroid hormone regulates the rat collagenase-3 promoter in osteoblastic cells through the cooperative interaction of the activator protein-1 site and the runt domain binding sequence. Selvamurugan, N., Chou, W.Y., Pearman, A.T., Pulumati, M.R., Partridge, N.C. J. Biol. Chem. (1998) [Pubmed]
  5. Longitudinal in vivo effects of growth hormone overexpression on bone in transgenic mice. Eckstein, F., Weusten, A., Schmidt, C., Wehr, U., Wanke, R., Rambeck, W., Wolf, E., Mohan, S. J. Bone Miner. Res. (2004) [Pubmed]
  6. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Komori, T., Yagi, H., Nomura, S., Yamaguchi, A., Sasaki, K., Deguchi, K., Shimizu, Y., Bronson, R.T., Gao, Y.H., Inada, M., Sato, M., Okamoto, R., Kitamura, Y., Yoshiki, S., Kishimoto, T. Cell (1997) [Pubmed]
  7. FIAT represses ATF4-mediated transcription to regulate bone mass in transgenic mice. Yu, V.W., Ambartsoumian, G., Verlinden, L., Moir, J.M., Prud'homme, J., Gauthier, C., Roughley, P.J., St-Arnaud, R. J. Cell Biol. (2005) [Pubmed]
  8. The Fos-related antigen Fra-1 is an activator of bone matrix formation. Eferl, R., Hoebertz, A., Schilling, A.F., Rath, M., Karreth, F., Kenner, L., Amling, M., Wagner, E.F. EMBO J. (2004) [Pubmed]
  9. A regulatory cascade involving retinoic acid, Cbfa1, and matrix metalloproteinases is coupled to the development of a process of perichondrial invasion and osteogenic differentiation during bone formation. Jiménez, M.J., Balbín, M., Alvarez, J., Komori, T., Bianco, P., Holmbeck, K., Birkedal-Hansen, H., López, J.M., López-Otín, C. J. Cell Biol. (2001) [Pubmed]
  10. Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. Weitzmann, M.N., Roggia, C., Toraldo, G., Weitzmann, L., Pacifici, R. J. Clin. Invest. (2002) [Pubmed]
  11. Chemogene therapy: osteocalcin promoter-based suicide gene therapy in combination with methotrexate in a murine osteosarcoma model. Cheon, J., Ko, S.C., Gardner, T.A., Shirakawa, T., Gotoh, A., Kao, C., Chung, L.W. Cancer Gene Ther. (1997) [Pubmed]
  12. Regulation of human osteocalcin promoter in hormone-independent human prostate cancer cells. Yeung, F., Law, W.K., Yeh, C.H., Westendorf, J.J., Zhang, Y., Wang, R., Kao, C., Chung, L.W. J. Biol. Chem. (2002) [Pubmed]
  13. DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Labrie, F., Bélanger, A., Luu-The, V., Labrie, C., Simard, J., Cusan, L., Gomez, J.L., Candas, B. Steroids (1998) [Pubmed]
  14. 1,25-dihydroxyvitamin D3 inhibits Osteocalcin expression in mouse through an indirect mechanism. Zhang, R., Ducy, P., Karsenty, G. J. Biol. Chem. (1997) [Pubmed]
  15. The mouse osteocalcin gene cluster contains three genes with two separate spatial and temporal patterns of expression. Desbois, C., Hogue, D.A., Karsenty, G. J. Biol. Chem. (1994) [Pubmed]
  16. Reciprocal temporospatial patterns of Msx2 and Osteocalcin gene expression during murine odontogenesis. Bidder, M., Latifi, T., Towler, D.A. J. Bone Miner. Res. (1998) [Pubmed]
  17. Effect of sustained gene delivery of platelet-derived growth factor or its antagonist (PDGF-1308) on tissue-engineered cementum. Anusaksathien, O., Jin, Q., Zhao, M., Somerman, M.J., Giannobile, W.V. J. Periodontol. (2004) [Pubmed]
  18. Expression of matrix proteins during the development of mineralized tissues. Sommer, B., Bickel, M., Hofstetter, W., Wetterwald, A. Bone (1996) [Pubmed]
  19. Identification of the cell type origin of odontoma-like cell masses in microphthalmic (mi/mi) mice by in situ hybridization. Nakajima, Y., Shimokawa, H., Terai, K., Onoue, H., Seino, Y., Tanaka, H., Sobue, S., Kitamura, Y., Nomura, S. Pathol. Int. (1996) [Pubmed]
  20. Differential gene expression between juvenile and adult dura mater: a window into what genes play a role in the regeneration of membranous bone. Wan, D.C., Aalami, O.O., Wang, Z., Nacamuli, R.P., Lorget, F., Derynck, R., Longaker, M.T. Plast. Reconstr. Surg. (2006) [Pubmed]
  21. Parathyroid hormone induction of the osteocalcin gene. Requirement for an osteoblast-specific element 1 sequence in the promoter and involvement of multiple-signaling pathways. Jiang, D., Franceschi, R.T., Boules, H., Xiao, G. J. Biol. Chem. (2004) [Pubmed]
  22. Antagonistic effects of transforming growth factor-beta on vitamin D3 enhancement of osteocalcin and osteopontin transcription: reduced interactions of vitamin D receptor/retinoid X receptor complexes with vitamin E response elements. Staal, A., Van Wijnen, A.J., Desai, R.K., Pols, H.A., Birkenhäger, J.C., Deluca, H.F., Denhardt, D.T., Stein, J.L., Van Leeuwen, J.P., Stein, G.S., Lian, J.B. Endocrinology (1996) [Pubmed]
  23. Menaquinone-7 regulates the expressions of osteocalcin, OPG, RANKL and RANK in osteoblastic MC3T3E1 cells. Katsuyama, H., Otsuki, T., Tomita, M., Fukunaga, M., Fukunaga, T., Suzuki, N., Saijoh, K., Fushimi, S., Sunami, S. Int. J. Mol. Med. (2005) [Pubmed]
  24. Expression of bone matrix proteins in urolithiasis model rats. Yasui, T., Fujita, K., Sasaki, S., Sato, M., Sugimoto, M., Hirota, S., Kitamura, Y., Nomura, S., Kohri, K. Urol. Res. (1999) [Pubmed]
  25. Analysis of osteocalcin expression in transgenic mice reveals a species difference in vitamin D regulation of mouse and human osteocalcin genes. Clemens, T.L., Tang, H., Maeda, S., Kesterson, R.A., Demayo, F., Pike, J.W., Gundberg, C.M. J. Bone Miner. Res. (1997) [Pubmed]
  26. Parathyroid hormone and parathyroid hormone-related protein exert both pro- and anti-apoptotic effects in mesenchymal cells. Chen, H.L., Demiralp, B., Schneider, A., Koh, A.J., Silve, C., Wang, C.Y., McCauley, L.K. J. Biol. Chem. (2002) [Pubmed]
  27. Cbfa1: a molecular switch in osteoblast biology. Ducy, P. Dev. Dyn. (2000) [Pubmed]
  28. Effect of KCA-098 on the function of osteoblast-like cells and the formation of TRAP-positive multinucleated cells in a mouse bone marrow cell population. Kawashima, K., Inoue, T., Tsutsumi, N., Endo, H. Biochem. Pharmacol. (1996) [Pubmed]
  29. Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts. Pirih, F.Q., Tang, A., Ozkurt, I.C., Nervina, J.M., Tetradis, S. J. Biol. Chem. (2004) [Pubmed]
  30. Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. Katagiri, T., Yamaguchi, A., Komaki, M., Abe, E., Takahashi, N., Ikeda, T., Rosen, V., Wozney, J.M., Fujisawa-Sehara, A., Suda, T. J. Cell Biol. (1994) [Pubmed]
  31. Overexpression of Phex in osteoblasts fails to rescue the Hyp mouse phenotype. Liu, S., Guo, R., Tu, Q., Quarles, L.D. J. Biol. Chem. (2002) [Pubmed]
  32. Effects on osteoclast and osteoblast activities in cultured mouse calvarial bones by synovial fluids from patients with a loose joint prosthesis and from osteoarthritis patients. Andersson, M.K., Lundberg, P., Ohlin, A., Perry, M.J., Lie, A., Stark, A., Lerner, U.H. Arthritis Res. Ther. (2007) [Pubmed]
  33. Characterization of Osf1, an osteoblast-specific transcription factor binding to a critical cis-acting element in the mouse Osteocalcin promoters. Schinke, T., Karsenty, G. J. Biol. Chem. (1999) [Pubmed]
  34. Multiple copies of the bone-specific osteocalcin gene in mouse and rat. Rahman, S., Oberdorf, A., Montecino, M., Tanhauser, S.M., Lian, J.B., Stein, G.S., Laipis, P.J., Stein, J.L. Endocrinology (1993) [Pubmed]
  35. CCAAT/enhancer-binding protein delta activates the Runx2-mediated transcription of mouse osteocalcin II promoter. Shin, C.S., Jeon, M.J., Yang, J.Y., Her, S.J., Kim, D., Kim, S.W., Kim, S.Y. J. Mol. Endocrinol. (2006) [Pubmed]
  36. Regulation of osteoblast differentiation by Nurr1 in MC3T3-E1 cell line and mouse calvarial osteoblasts. Lee, M.K., Choi, H., Gil, M., Nikodem, V.M. J. Cell. Biochem. (2006) [Pubmed]
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