Osteocalcin Explained

Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid^[1]) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein.^[2]

Because osteocalcin has gla domains, its synthesis is vitamin K dependent. In humans, osteocalcin is encoded by the BGLAP gene.^{[3] [4]} Its receptors include GPRC6A, GPR158, and possibly a third, yet-to-be-identified receptor.^{[5] [6]} There is evidence that GPR37 might be the third osteocalcin receptor.^[7]

Function

Osteocalcin is secreted solely by osteoblasts and thought to play a role in the body's metabolic regulation. 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.^[8]

• In the pancreas, osteocalcin acts on beta cells, causing beta cells in the pancreas to release more insulin.
• In fat cells, osteocalcin triggers the release of the hormone adiponectin, which increases sensitivity to insulin.^[9]
• In muscle, osteocalcin acts on myocytes to promote energy availability and utilization and in this manner favors exercise capacity.^{[10] [11]}
• In the testes, osteocalcin acts on Leydig cells, stimulating testosterone biosynthesis and therefore affects male fertility.^[12]
• In the brain, osteocalcin plays an important role in development and functioning including spatial learning and memory.^[13]

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.^[14]

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.^[15]

Further reading

• Kamdem LK, Hamilton L, Cheng C, Liu W, Yang W, Johnson JA, Pui CH, Relling MV . Genetic predictors of glucocorticoid-induced hypertension in children with acute lymphoblastic leukemia . Pharmacogenetics and Genomics . 18 . 6 . 507–14 . June 2008 . 18496130 . 10.1097/FPC.0b013e3282fc5801 . 1251203 .
• Lin GT, Tseng HF, Chang CK, Chuang LY, Liu CS, Yang CH, Tu CJ, Wang EC, Tan HF, Chang CC, Wen CH, Chen HC, Chang HW . SNP combinations in chromosome-wide genes are associated with bone mineral density in Taiwanese women . The Chinese Journal of Physiology . 51 . 1 . 32–41 . February 2008 . 18551993 .
• Lumachi F, Camozzi V, Tombolan V, Luisetto G . 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 . E64-7 . September 2009 . Suppl 1 . 19751417 . 10.1111/j.1749-6632.2009.04955.x . 2009NYASA1173...64L . 9796894 .
• Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Yano S, Sugimoto T . 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 . September 2009 . 19641839 . 10.1007/s00223-009-9272-4 . 21508194 .
• Makita N, Suzuki M, Asami S, Takahata R, Kohzaki D, Kobayashi S, Hakamazuka T, Hozumi N . Two of four alternatively spliced isoforms of RUNX2 control osteocalcin gene expression in human osteoblast cells . Gene . 413 . 1–2 . 8–17 . April 2008 . 18321663 . 10.1016/j.gene.2007.12.025 .
• Desbois C, Karsenty G . Osteocalcin cluster: implications for functional studies . Journal of Cellular Biochemistry . 57 . 3 . 379–83 . March 1995 . 7768973 . 10.1002/jcb.240570302 . 130765 .
• Salem AM, Zohny SF, Abd El-Wahab MM, Hamdy R . Predictive value of osteocalcin and beta-CrossLaps in metastatic breast cancer . Clinical Biochemistry . 40 . 16–17 . 1201–8 . November 2007 . 17889845 . 10.1016/j.clinbiochem.2007.07.006 .
• Im JA, Yu BP, Jeon JY, Kim SH . Relationship between osteocalcin and glucose metabolism in postmenopausal women . Clinica Chimica Acta; International Journal of Clinical Chemistry . 396 . 1–2 . 66–9 . October 2008 . 18657532 . 10.1016/j.cca.2008.07.001 .
• Ba Y, Huang H, Yang Y, Cui L, Zhu J, Zhu C, Liu J, Zhang Y . 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 . November 2009 . 19767102 . 10.1016/j.ecoenv.2009.08.014 . 2009EcoES..72.2158B .
• Hwang YC, Jeong IK, Ahn KJ, Chung HY . 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 . November 2009 . 19877133 . 10.1002/dmrr.1045 . 39181400 .
• Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, Ensrud KE, Nestlerode CS, Marshall LM, Hoffman AR, Lewis C, Lang TF, Barrett-Connor E, Ferrell RE, Orwoll ES, Zmuda JM . 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 . December 2009 . 19453261 . 2791518 . 10.1359/jbmr.090524 .
• Yu S, Jiang Y, Galson DL, Luo M, Lai Y, Lu Y, Ouyang HJ, Zhang J, Xiao G . 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 . February 2008 . 18171674 . 2736298 . 10.1074/jbc.M705653200 . free .
• Kayed H, Bekasi S, Keleg S, Michalski CW, Giese T, Friess H, Kleeff J . BGLAP is expressed in pancreatic cancer cells and increases their growth and invasion . Molecular Cancer . 6 . 83 . December 2007 . 18163903 . 2245975 . 10.1186/1476-4598-6-83 . free .
• French D, Hamilton LH, Mattano LA, Sather HN, Devidas M, Nachman JB, Relling MV . 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 . May 2008 . 18285546 . 2343589 . 10.1182/blood-2007-11-123885 .
• Pittas AG, Harris SS, Eliades M, Stark P, Dawson-Hughes B . Association between serum osteocalcin and markers of metabolic phenotype . The Journal of Clinical Endocrinology and Metabolism . 94 . 3 . 827–32 . March 2009 . 19088165 . 2681283 . 10.1210/jc.2008-1422 .
• Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellström D . 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 . May 2009 . 19063687 . 10.1359/jbmr.081234 . 207269385 .
• Wahlgren CM, Zheng W, Shaalan W, Tang J, Bassiouny HS . 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 . 2009 . 19136823 . 10.1159/000189204 . 34370256 .
• Lumachi F, Ermani M, Camozzi V, Tombolan V, Luisetto G . 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 . E60-3 . September 2009 . Suppl 1 . 19751416 . 10.1111/j.1749-6632.2009.04953.x . 2009NYASA1173...60L . 11577/2430145 . 1149818 .
• Born AK, Rottmar M, Lischer S, Pleskova M, Bruinink A, Maniura-Weber K . Correlating cell architecture with osteogenesis: first steps towards live single cell monitoring . European Cells & Materials . 18 . 49–60, 61–2; discussion 60 . October 2009 . 19856264 .
• Fujisawa R . [Recent advances in research on bone matrix proteins] . Nihon Rinsho. Japanese Journal of Clinical Medicine . 60 . 72–8 . March 2002 . Suppl 3 . 11979972 .

Notes and References

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