Osteocalcin

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]

BGLAP
Identifiers
AliasesBGLAP, BGP, OC, OCN, bone gamma-carboxyglutamate protein, Osteocalcin
External IDsOMIM: 112260 MGI: 88155 HomoloGene: 104130 GeneCards: BGLAP
Orthologs
SpeciesHumanMouse
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 MbChr 3: 88.28 – 88.28 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Not to be confused with Osteonectin or Osteopontin.

Because osteocalcin has gla domains, its synthesis is vitamin K 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 thought to play a role in the body's metabolic regulation.[12] In its carboxylated form it binds calcium directly and thus concentrates in bone.

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 hormone adiponectin, which increases sensitivity to insulin.[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 therefore affects 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 osteocalcin is produced by osteoblasts, it is often used as a marker for the bone formation process. It has been observed that higher serum osteocalcin levels are relatively well correlated 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 on the effectiveness of a given drug on bone formation. For instance, one study which aimed to study the effectiveness of a glycoprotein called lactoferrin on bone formation used osteocalcin as a measure of 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, P. V.; Carr, S. A.; Biemann, K. (1982). "Primary structure of monkey osteocalcin". Biochemistry. 21 (4): 638–42. 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): 426–34. 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, Chen Y, Li X (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, Amber (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, Horvath T, Domingos A, Marsland A, Yadav V, Rahmouni K, Gao X, Karsenty G (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
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