Alternative titles; symbols
HGNC Approved Gene Symbol: BGLAP
Cytogenetic location: 1q22 Genomic coordinates (GRCh38): 1:156,242,184-156,243,317 (from NCBI)
Bone gamma-carboxyglutamic acid (Gla) protein (BGLAP, or BGP) is a small, highly conserved molecule associated with the mineralized matrix of bone. Its interaction with synthetic hydroxyapatite in vitro is absolutely dependent on its content of 3 residues of gamma-carboxyglutamic acid, the amino acid formed posttranslationally from glutamic acid by a vitamin K-dependent process. Pan and Price (1985) studied cDNA of the rat protein. They found that a stretch of 9 residues proximal to the NH2-terminus of secreted BGP is strikingly similar to the corresponding regions in known propeptides of the gamma-carboxyglutamic acid-containing blood coagulation factors. They suggested that this common structural feature may be involved in the posttranslational targeting of these polypeptides for vitamin K-dependent gamma-carboxylation.
Celeste et al. (1986) used mouse and rat cDNA clones to isolate the human BGP gene. The deduced prepropeptide contains 98 amino acids and has a 49-amino acid N-terminal leader sequence.
Jung et al. (2001) stated that the osteocalcin (OC) propeptide contains 100 amino acids. Northern blot analysis of human tissues detected a major OC transcript of between 1.0 and 1.2 kb with strong expression in ovary, prostate, testis, skeletal muscle, and thyroid, and moderate to weak expression in most other tissues. A transcript of about 450 bp showed strong expression only in bone marrow with weak expression in trachea, spinal cord, small intestine, and colon. RT-PCR detected 6 OC splice variants that retained a different combination of introns, and the dominant transcript contained all 3 introns. These 6 variants encode proteins of either 57 or 100 amino acids that are identical to preproosteocalcin at the N terminus. Only bone-related tissue efficiently spliced out all 3 OC introns. In prostate tumor epithelial cells, inefficiently spliced OC RNA predominated, and little OC protein was detected. However, the completely spliced form dominated in tumors that had metastasized to bone, suggesting that there may be bone-specific splicing factors.
Laize et al. (2005) stated that BGP is a 5.6-kD protein that contains a signal peptide, followed by a propeptide sequence, a gamma- glutamyl carboxylase (GGCX; 137167) recognition site, and a Gla domain. BGP also has an intramolecular disulfide bond within the Gla domain and a proteolytic cleavage site following the GGCX-recognition motif.
Kerner et al. (1989) described regions within the BGP promoter that contribute to basal expression of the osteocalcin gene in osteoblast-like cells in culture. Further, they defined a 21-bp element that acts in cis to mediate vitamin D inducibility of the osteocalcin gene.
Crystal Structure
Hoang et al. (2003) determined the X-ray crystal structure of porcine osteocalcin at 2.0-angstrom resolution, which revealed a negatively charged protein surface that coordinates 5 calcium ions in a spatial orientation that is complementary to calcium ions in a hydroxyapatite crystal lattice.
Celeste et al. (1986) determined that the human BGP gene contains 4 exons. Comparison of the exon structure of the BGP gene and the factor IX gene (300746), which is a gamma-carboxylated clotting factor, suggested that the exons encoding the part of the leader peptides presumably directing gamma-carboxylation arose from a common ancestral sequence.
Puchacz et al. (1989) assigned the osteocalcin gene to chromosome 1 by Southern blot analysis of DNAs from a panel of mouse-human somatic cell hybrids. Furthermore, by Southern blot analysis of DNAs from mouse-human hybrids that retain specific segments of human chromosome 1, they determined that the locus is on 1q, telomeric to the alpha-spectrin gene (182860). Johnson et al. (1991) mapped the Bglap gene to mouse chromosome 3 by study of somatic whole-cell hybrids and microcell hybrids. Desbois et al. (1994) confirmed this assignment by analyzing the segregation of restriction fragment length variants (RFLVs) in an interspecific backcross.
Raymond et al. (1999) stated that the BGLAP gene maps to chromosome 1q25-q31.
Laize et al. (2005) identified orthologs of BGP and the related gene MGP (154870) only in vertebrates and cartilaginous fish. The MGP and BGP genes appeared to originate from 2 genome duplications that occurred around 500 and 400 million years ago before jawless and jawed fish evolved, respectively. MGP appeared concomitantly with the emergence of cartilaginous structures, and BGP, derived from MGP, appeared thereafter along with bony structures.
See 277450 and 118650 for a discussion of chondrodysplasia punctata, coagulation defects, and coumarin embryopathy which have, it seems, a common link in BGP.
See 277440 for a discussion of the work of Morrison et al. (1992) indicating that allelic variation in the vitamin D receptor gene is related to serum concentrations of osteocalcin and in turn probably to bone density.
The 1-alpha,25-dihydroxyvitamin D3 (VD3)-dependent stimulation of BGP gene transcription in bone tissue is mediated by interactions of trans-activating factors with distinct VD3-responsive elements (VDREs). To determine the identity of endogenous VD3-induced complexes recognizing the BGP-VDREs in osteoblasts, Staal et al. (1996) performed gel shift immunoassays with nuclear proteins from osteoblastic cells using a panel of monoclonal antibodies. They showed that VD3-inducible complexes interacting with the BGP-VDREs represent 2 distinct heterodimeric complexes, each composed of the vitamin D receptor (VDR) and the retinoid X receptor-alpha (RXR). The BGP-VDR/RXR-alpha heterodimers are immunoreactive with RXR antibodies and several antibodies directed against the ligand-binding domain of the VDR. The OC-VDRE complex is also efficiently recognized by specific monoclonal antibodies containing epitopes in or near the VDR DNA-binding domain (between amino acids 57-164) which may reflect specialized requirements for VD3 regulation of BGP gene expression in response to physiologic cues mediating osteoblast differentiation.
It is likely that differentiation along the osteoblast lineage involves osteoblast-specific transcription factors (OSFs). In search of OSFs, Ducy and Karsenty (1995) and others studied the regulation of expression of osteocalcin, which is the only gene that is expressed in osteoblasts but not in other extracellular matrix (ECM)-producing cell types. They characterized a cis-acting element, termed OSE2, in the promoter of the mouse osteocalcin gene 2 that bound a factor present only in osteoblast nuclear extracts and conferred osteoblast-specific activity on a heterologous promoter. Analysis of Osf2, the osteoblast nuclear protein that binds to OSE2, showed that it is immunologically related to the Cbfa transcription factors (e.g., CBFA1; 600211). Ducy et al. (1997) cloned the cDNA encoding Osf2/Cbfa1. They showed that its expression is initiated in the mesenchymal condensations of the developing skeleton, is strictly restricted to cells of the osteoblast lineage thereafter, and is regulated by bone morphogenetic protein-7 (BMP7; 112267) and vitamin D3. It binds to and regulates the expression of multiple genes expressed in osteoblasts. Finally, forced expression of Osf2/Cbfa1 in nonosteoblastic cells induced the expression of the principal osteoblast-specific genes. Nonsense and missense mutations in the OSF2/CBFA1 gene are responsible for cleidocranial dysplasia (CCD; 119600).
To identify genes influencing variation in serum osteocalcin (BGP) levels, Mitchell et al. (2000) conducted a genomewide scan in 429 individuals comprising 10 large multigenerational families. BGP levels were measured by immunoassay, and genetic markers were typed at approximately 10-cM intervals across the genome. The heritability of BGP levels in this population was 62 +/- 8%. The authors detected significant evidence for linkage between a quantitative trait locus influencing serum BGP levels and markers on chromosome 16q, and suggestive evidence for linkage of BGP levels with markers on chromosome 20q. The multipoint lod scores peaked at 3.35 on chromosome 16 and 2.78 on chromosome 20, corresponding to P values of 0.00004 and 0.00017, respectively. A potential candidate gene for bone formation in the linked region on chromosome 20 is CDMP1 (601146), which encodes cartilage-derived morphogenetic protein-1.
Hassan et al. (2004) found that Msx2 (123101), Dlx3 (600525), Dlx5 (600028), and Runx2 (600211) regulated the expression of osteocalcin (OC) and the control of bone formation in mouse embryo. Msx2 associated with transcriptionally repressed OC chromatin, and Dlx3 and Dlx5 were recruited with Runx2 to initiate OC transcription. In a second regulatory switch, Dlx3 association decreased and Dlx5 recruitment increased coincident with the mineralization stage of osteoblast differentiation. The appearance of Dlx3 followed by Dlx5 in the OC promoter correlated with increased transcription represented by increased occupancy of RNA polymerase II.
Using isolated mouse pancreatic islets, a beta cell line, and primary mouse adipocytes, Ferron et al. (2008) showed that picomolar amounts of osteocalcin affected insulin secretion and beta-cell proliferation. Nanomolar amounts altered adipocyte gene expression and reduced the development of obesity and diabetes in wildtype mice raised under conditions favoring the appearance of these diseases.
Chowdhury et al. (2020) found that IL6 (147620) regulated circulating osteocalcin levels in response to training intervention in humans. Further analyses with mouse models showed that the majority of Il6 molecules present in general circulation during exercise originated from muscle. Muscle-derived Il6 enhanced exercise capacity by signaling in osteoblasts to promote osteoclast differentiation and release of osteocalcin in general circulation. Muscle-derived Il6 also favored uptake and catabolism of glucose and fatty acid in myofibers during exercise through osteocalcin.
Raymond et al. (1999) genotyped 140 healthy postmenopausal women (70 with bone mineral density (BMD) levels in the lowest quartile for a similar age population and 70 with BMD levels in the highest quartile) for short tandem repeat (STR) markers in the osteocalcin locus and identified a significant difference between allele frequency distributions of cases and controls with marker D1S3737 (p = 0.007). Logistic regression analysis showed that 1 allele of D1S3737 was associated with BMD status in this population (p = 0.03). Raymond et al. (1999) suggested that genetic variation at the osteocalcin locus impacts BMD levels in the postmenopausal period and may predispose some women to osteoporosis.
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Pan, L. C., Price, P. A. The propeptide of rat bone gamma-carboxyglutamic acid protein shares homology with other vitamin K-dependent protein precursors. Proc. Nat. Acad. Sci. 82: 6109-6113, 1985. [PubMed: 3875856] [Full Text: https://doi.org/10.1073/pnas.82.18.6109]
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Staal, A., van Wijnen, A. J., Birkenhager, J. C., Pols, H. A. P., Prahl, J., DeLuca, H., Gaub, M.-P., Lian, J. B., Stein, G. S., van Leeuwen, J. P. T. M., Stein, J. L. Distinct conformations of vitamin D receptor/retinoid X receptor-alpha heterodimers are specified by dinucleotide differences in the vitamin D-responsive elements of the osteocalcin and osteopontin genes. Molec. Endocr. 10: 1444-1456, 1996. [PubMed: 8923469] [Full Text: https://doi.org/10.1210/mend.10.11.8923469]