Osteocalcin

Not to be confused with Osteonectin or Osteopontin.

BGLAP
Identifiers
Aliases	BGLAP , BGP, OC, OCN, bone gamma-carboxyglutamate protein, Osteocalcin
External IDs	OMIM: 112260; MGI: 88155; HomoloGene: 104130; GeneCards: BGLAP; OMA:BGLAP - orthologs
Gene location (Human) Chr. Chromosome 1 (human) [1] Band 1q22 Start 156,242,184 bp [1] End 156,243,317 bp [1]
Gene location (Mouse) Chr. Chromosome 3 (mouse) [2] Band 3 F1|3 38.81 cM Start 88,275,923 bp [2] End 88,280,050 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle gonad right hemisphere of cerebellum C1 segment muscle layer of sigmoid colon putamen substantia nigra caudate nucleus nucleus accumbens right uterine tube Top expressed in esophagus cochlea lip placenta lymph node stomach white adipose tissue thyroid gland morula bone marrow More reference expression data BioGPS n/a
Gene ontology Molecular function calcium ion binding structural molecule activity metal ion binding hydroxyapatite binding structural constituent of bone Cellular component cytoplasm perikaryon rough endoplasmic reticulum Golgi apparatus cell projection endoplasmic reticulum lumen extracellular region dendrite Golgi lumen extracellular space vesicle Biological process skeletal system development bone mineralization response to vitamin D response to organic cyclic compound ossification response to testosterone regulation of bone mineralization biomineral tissue development cellular response to growth factor stimulus response to mechanical stimulus ageing response to zinc ion response to glucocorticoid cellular response to vitamin D response to activity response to estrogen odontogenesis endoplasmic reticulum to Golgi vesicle-mediated transport response to gravity response to vitamin K response to hydroxyisoflavone cell adhesion response to nutrient levels regulation of osteoclast differentiation osteoblast differentiation response to inorganic substance osteoblast development response to ethanol regulation of bone resorption bone development regulation of cellular response to insulin stimulus Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 632 12095 Ensembl ENSG00000242252 ENSMUSG00000074489 UniProt P02818 P54615 RefSeq (mRNA) NM_199173 NM_031368 NM_001305448 NM_001305449 NM_001305450 RefSeq (protein) NP_954642 NP_001292377 NP_001292378 NP_001292379 NP_112736 Location (UCSC) Chr 1: 156.24 – 156.24 Mb Chr 3: 88.28 – 88.28 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid ^[5] ) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein. ^[6]

Because osteocalcin has gla domains, its synthesis is vitamin K2-dependent. In humans, osteocalcin is encoded by the BGLAP gene. ^{[7] [8]} Its receptors include GPRC6A, GPR158, and possibly a third, yet-to-be-identified receptor. ^{[9] [10]} There is evidence that GPR37 might be the third osteocalcin receptor. ^[11]

Function

Osteocalcin is secreted solely by osteoblasts and is thought to play a role in the body's metabolic regulation. ^[12] In its carboxylated form, calcium is bound directly to the bone and thus concentrates here.

In its uncarboxylated form, osteocalcin acts as a hormone in the body, signalling in the pancreas, fat, muscle, testes, and brain. ^[13]

• In the pancreas, osteocalcin acts on beta cells, causing beta cells in the pancreas to release more insulin. ^[12]
• In fat cells, osteocalcin triggers the release of the adiponectin hormone, which increases insulin sensitivity. ^[12]
• In muscle, osteocalcin acts on myocytes to promote energy availability and utilization and, in this manner, favors exercise capacity. ^{[14] [15]}
• In the testes, osteocalcin acts on Leydig cells, stimulating testosterone biosynthesis and affecting male fertility. ^[16]
• In the brain, osteocalcin plays an important role in development and functioning, including spatial learning and memory. ^[17]

An acute stress response (ASR), colloquially known as the fight-or-flight response, stimulates osteocalcin release from bone within minutes in mice, rats, and humans. Injections of high levels of osteocalcin alone can trigger an ASR in the presence of adrenal insufficiency. ^[18]

Use as a biochemical marker for bone formation

As osteoblasts produce osteocalcin, it is often used as a marker for the bone formation process. Higher serum osteocalcin levels have been observed to correlate relatively well with increases in bone mineral density during treatment with anabolic bone formation drugs for osteoporosis, such as teriparatide. In many studies, osteocalcin is used as a preliminary biomarker for the effectiveness of a given drug on bone formation. For instance, one study that aimed to study the efficacy of a glycoprotein called lactoferrin on bone formation used osteocalcin to measure osteoblast activity. ^[19]

References

1. GRCh38: Ensembl release 89: ENSG00000242252 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000074489 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Hauschka PV, Carr SA, Biemann K (February 1982). "Primary structure of monkey osteocalcin". Biochemistry. 21 (4): 638–642. doi:10.1021/bi00533a006. PMID   6978733.
6. Hauschka PV, Reid ML (August 1978). "Timed appearance of a calcium-binding protein containing gamma-carboxyglutamic acid in developing chick bone". Developmental Biology. 65 (2): 426–434. doi:10.1016/0012-1606(78)90038-6. PMID   680371.
7. Puchacz E, Lian JB, Stein GS, Wozney J, Huebner K, Croce C (May 1989). "Chromosomal localization of the human osteocalcin gene". Endocrinology. 124 (5): 2648–50. doi:10.1210/endo-124-5-2648. PMID   2785029.
8. Cancela L, Hsieh CL, Francke U, Price PA (September 1990). "Molecular structure, chromosome assignment, and promoter organization of the human matrix Gla protein gene". The Journal of Biological Chemistry. 265 (25): 15040–8. doi: 10.1016/S0021-9258(18)77221-9 . PMID   2394711.
9. Pi M, Wu Y, Quarles LD (July 2011). "GPRC6A mediates responses to osteocalcin in β-cells in vitro and pancreas in vivo". Journal of Bone and Mineral Research. 26 (7): 1680–3. doi:10.1002/jbmr.390. PMC   5079536 . PMID   21425331.
10. Berger JM, Singh P, Khrimian L, Morgan DA, Chowdhury S, Arteaga-Solis E, et al. (September 2019). "Mediation of the Acute Stress Response by the Skeleton". Cell Metabolism. 30 (5): 890–902.e8. doi:10.1016/j.cmet.2019.08.012. PMC   6834912 . PMID   31523009.
11. Qian Z, Li H, Yang H, Yang Q, Lu Z, Wang L, et al. (October 2021). "Osteocalcin attenuates oligodendrocyte differentiation and myelination via GPR37 signaling in the mouse brain". Science Advances. 7 (43): eabi5811. Bibcode:2021SciA....7.5811Q. doi:10.1126/sciadv.abi5811. PMC   8535816 . PMID   34678058.
12. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. (August 2007). "Endocrine regulation of energy metabolism by the skeleton". Cell. 130 (3): 456–69. doi:10.1016/j.cell.2007.05.047. PMC   2013746 . PMID   17693256.
13. Karsenty G, Olson EN (March 2016). "Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication". Cell. 164 (6): 1248–1256. doi:10.1016/j.cell.2016.02.043. PMC   4797632 . PMID   26967290.
14. Mera P, Laue K, Ferron M, Confavreux C, Wei J, Galán-Díez M, et al. (June 2016). "Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise". Cell Metabolism. 23 (6): 1078–1092. doi:10.1016/j.cmet.2016.05.004. PMC   4910629 . PMID   27304508.
15. Dance A (23 February 2022). "Fun facts about bones: More than just scaffolding" . Knowable Magazine. doi: 10.1146/knowable-022222-1 . Retrieved 8 March 2022.
16. Karsenty G, Oury F (January 2014). "Regulation of male fertility by the bone-derived hormone osteocalcin". Molecular and Cellular Endocrinology. 382 (1): 521–526. doi:10.1016/j.mce.2013.10.008. PMC   3850748 . PMID   24145129.
17. Obri A, Khrimian L, Karsenty G, Oury F (March 2018). "Osteocalcin in the brain: from embryonic development to age-related decline in cognition". Nature Reviews. Endocrinology. 14 (3): 174–182. doi:10.1038/nrendo.2017.181. PMC   5958904 . PMID   29376523.
18. Meyer-Berger J, Singh P, Khrimian L, Morgan D, Chowdhury S, Arteaga-Solis E, et al. (2019). "Mediation of the Acute Stress Response by the Skeleton". Cell Metabolism. 30 (5): 890–902.e8. doi:10.1016/j.cmet.2019.08.012. PMC   6834912 . PMID   31523009.
19. Bharadwaj S, Naidu AG, Betageri GV, Prasadarao NV, Naidu AS (September 2009). "Milk ribonuclease-enriched lactoferrin induces positive effects on bone turnover markers in postmenopausal women". Osteoporosis International. 20 (9): 1603–11. doi:10.1007/s00198-009-0839-8. PMID   19172341. S2CID   10711802.

Further reading

• Kamdem LK, Hamilton L, Cheng C, Liu W, Yang W, Johnson JA, et al. (June 2008). "Genetic predictors of glucocorticoid-induced hypertension in children with acute lymphoblastic leukemia". Pharmacogenetics and Genomics. 18 (6): 507–14. doi:10.1097/FPC.0b013e3282fc5801. PMID   18496130. S2CID   1251203.
• Lin GT, Tseng HF, Chang CK, Chuang LY, Liu CS, Yang CH, et al. (February 2008). "SNP combinations in chromosome-wide genes are associated with bone mineral density in Taiwanese women". The Chinese Journal of Physiology. 51 (1): 32–41. PMID   18551993.
• Lumachi F, Camozzi V, Tombolan V, Luisetto G (September 2009). "Bone mineral density, osteocalcin, and bone-specific alkaline phosphatase in patients with insulin-dependent diabetes mellitus". Annals of the New York Academy of Sciences. 1173 (Suppl 1): E64-7. Bibcode:2009NYASA1173...64L. doi:10.1111/j.1749-6632.2009.04955.x. PMID   19751417. S2CID   9796894.
• Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Yano S, Sugimoto T (September 2009). "Serum osteocalcin/bone-specific alkaline phosphatase ratio is a predictor for the presence of vertebral fractures in men with type 2 diabetes". Calcified Tissue International. 85 (3): 228–34. doi:10.1007/s00223-009-9272-4. PMID   19641839. S2CID   21508194.
• Makita N, Suzuki M, Asami S, Takahata R, Kohzaki D, Kobayashi S, et al. (April 2008). "Two of four alternatively spliced isoforms of RUNX2 control osteocalcin gene expression in human osteoblast cells". Gene. 413 (1–2): 8–17. doi:10.1016/j.gene.2007.12.025. PMID   18321663.
• Desbois C, Karsenty G (March 1995). "Osteocalcin cluster: implications for functional studies". Journal of Cellular Biochemistry. 57 (3): 379–83. doi:10.1002/jcb.240570302. PMID   7768973. S2CID   130765.
• Salem AM, Zohny SF, Abd El-Wahab MM, Hamdy R (November 2007). "Predictive value of osteocalcin and beta-CrossLaps in metastatic breast cancer". Clinical Biochemistry. 40 (16–17): 1201–8. doi:10.1016/j.clinbiochem.2007.07.006. PMID   17889845.
• Im JA, Yu BP, Jeon JY, Kim SH (October 2008). "Relationship between osteocalcin and glucose metabolism in postmenopausal women". Clinica Chimica Acta; International Journal of Clinical Chemistry. 396 (1–2): 66–9. doi:10.1016/j.cca.2008.07.001. PMID   18657532.
• Ba Y, Huang H, Yang Y, Cui L, Zhu J, Zhu C, et al. (November 2009). "The association between osteocalcin gene polymorphism and dental fluorosis among children exposed to fluoride in People's Republic of China". Ecotoxicology and Environmental Safety. 72 (8): 2158–61. Bibcode:2009EcoES..72.2158B. doi:10.1016/j.ecoenv.2009.08.014. PMID   19767102.
• Hwang YC, Jeong IK, Ahn KJ, Chung HY (November 2009). "The uncarboxylated form of osteocalcin is associated with improved glucose tolerance and enhanced beta-cell function in middle-aged male subjects". Diabetes/Metabolism Research and Reviews. 25 (8): 768–72. doi:10.1002/dmrr.1045. PMID   19877133. S2CID   39181400.
• Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, et al. (December 2009). "High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men". Journal of Bone and Mineral Research. 24 (12): 2039–49. doi:10.1359/jbmr.090524. PMC   2791518 . PMID   19453261.
• Yu S, Jiang Y, Galson DL, Luo M, Lai Y, Lu Y, et al. (February 2008). "General transcription factor IIA-gamma increases osteoblast-specific osteocalcin gene expression via activating transcription factor 4 and runt-related transcription factor 2". The Journal of Biological Chemistry. 283 (9): 5542–53. doi: 10.1074/jbc.M705653200 . PMC   2736298 . PMID   18171674.
• Kayed H, Bekasi S, Keleg S, Michalski CW, Giese T, Friess H, et al. (December 2007). "BGLAP is expressed in pancreatic cancer cells and increases their growth and invasion". Molecular Cancer. 6: 83. doi: 10.1186/1476-4598-6-83 . PMC   2245975 . PMID   18163903.
• French D, Hamilton LH, Mattano LA, Sather HN, Devidas M, Nachman JB, et al. (May 2008). "A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group". Blood. 111 (9): 4496–9. doi:10.1182/blood-2007-11-123885. PMC   2343589 . PMID   18285546.
• Pittas AG, Harris SS, Eliades M, Stark P, Dawson-Hughes B (March 2009). "Association between serum osteocalcin and markers of metabolic phenotype". The Journal of Clinical Endocrinology and Metabolism. 94 (3): 827–32. doi:10.1210/jc.2008-1422. PMC   2681283 . PMID   19088165.
• Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, et al. (May 2009). "Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men". Journal of Bone and Mineral Research. 24 (5): 785–91. doi:10.1359/jbmr.081234. PMID   19063687. S2CID   207269385.
• Wahlgren CM, Zheng W, Shaalan W, Tang J, Bassiouny HS (2009). "Human carotid plaque calcification and vulnerability. Relationship between degree of plaque calcification, fibrous cap inflammatory gene expression and symptomatology". Cerebrovascular Diseases. 27 (2): 193–200. doi:10.1159/000189204. PMID   19136823. S2CID   34370256.
• Lumachi F, Ermani M, Camozzi V, Tombolan V, Luisetto G (September 2009). "Changes of bone formation markers osteocalcin and bone-specific alkaline phosphatase in postmenopausal women with osteoporosis". Annals of the New York Academy of Sciences. 1173 (Suppl 1): E60-3. Bibcode:2009NYASA1173...60L. doi:10.1111/j.1749-6632.2009.04953.x. hdl:11577/2430145. PMID   19751416. S2CID   1149818.
• Born AK, Rottmar M, Lischer S, Pleskova M, Bruinink A, Maniura-Weber K (October 2009). "Correlating cell architecture with osteogenesis: first steps towards live single cell monitoring". European Cells & Materials. 18: 49–60, 61–2, discussion 60. PMID   19856264.
• Fujisawa R (March 2002). "[Recent advances in research on bone matrix proteins]". Nihon Rinsho. Japanese Journal of Clinical Medicine. 60 (Suppl 3): 72–8. PMID   11979972.

External links

• Osteocalcin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt : Q8HYY9 (Pig Osteocalcin) at the PDBe-KB .