Osteocalcin: A Protein Hormone Connecting Metabolism, Bone and Testis Function

Author(s): Luca De Toni, Kenda Jawich, Maurizio De Rocco Ponce, Andrea Di Nisio, Carlo Foresta*

Journal Name: Protein & Peptide Letters

Volume 27 , Issue 12 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

During the last decade, the disclosure of systemic effects of osteocalcin (OCN) in its undercarboxylated form contributed to switch the concept of bone from a merely structural apparatus to a fully endocrine organ involved in the regulation of systemic functions. Since that time, the role of OCN as osteokine has been more and more widened appreciated and detailed by the major use of animal models, starting from the original function in the bone extracellular matrix as Gla-protein and spanning from the protective effects towards weight gain, insulin sensitivity and glucose homeostasis, to the anabolic and metabolic roles in skeletal muscle, to the stimulating effects on the testis endocrine function and male fertility, to the most recent preservation from anxious and depressive states through a direct activity on the central nervous system. In this review, experimental data supporting the inter-organ communication roles of this protein are discussed, together with the available data supporting the consistency between experimental data obtained in animals and those reported in humans. In addition, a specific session has been devoted to the possible significance the OCN as a template agonist on its receptor GPRC6A, for the development of novel therapeutic and pharmacological approaches for the treatment of dismetabolic states and male infertility.

Keywords: Osteokine, decarboxylation, GPRC6A, testosterone, insulin, peptide agonist.

[1]
Castillo-Armengol, J.; Fajas, L.; Lopez-Mejia, I.C. Inter-organ communication: A gatekeeper for metabolic health. EMBO Rep., 2019, 20(9), e47903.
[http://dx.doi.org/10.15252/embr.201947903] [PMID: 31423716]
[2]
Rosen, C.J. Bone remodeling, energy metabolism, and the molecular clock. Cell Metab., 2008, 7(1), 7-10.
[http://dx.doi.org/10.1016/j.cmet.2007.12.004] [PMID: 18177720]
[3]
Nakashima, T.; Hayashi, M.; Takayanagi, H. New insights into osteoclastogenic signaling mechanisms. Trends Endocrinol. Metab., 2012, 23(11), 582-590.
[http://dx.doi.org/10.1016/j.tem.2012.05.005] [PMID: 22705116]
[4]
Ducy, P.; Schinke, T.; Karsenty, G. The osteoblast: A sophisticated fibroblast under central surveillance. Science, 2000, 289(5484), 1501-1504.
[http://dx.doi.org/10.1126/science.289.5484.1501] [PMID: 10968779]
[5]
Karsenty, G.; Kronenberg, H.M.; Settembre, C. Genetic control of bone formation. Annu. Rev. Cell Dev. Biol., 2009, 25, 629-648.
[http://dx.doi.org/10.1146/annurev.cellbio.042308.113308] [PMID: 19575648]
[6]
Karsenty, G.; Ferron, M. The contribution of bone to whole-organism physiology. Nature, 2012, 481(7381), 314-320.
[http://dx.doi.org/10.1038/nature10763] [PMID: 22258610]
[7]
Oury, F. A crosstalk between bone and gonads. Ann. N. Y. Acad. Sci., 2012, 1260, 1-7.
[http://dx.doi.org/10.1111/j.1749-6632.2011.06360.x] [PMID: 22239174]
[8]
Price, P.A.; Otsuka, A.A.; Poser, J.W.; Kristaponis, J.; Raman, N. Characterization of a γ-carboxyglutamic acid-containing protein from bone. Proc. Natl. Acad. Sci. USA, 1976, 73(5), 1447-1451.
[http://dx.doi.org/10.1073/pnas.73.5.1447] [PMID: 1064018]
[9]
Hauschka, P.V.; Lian, J.B.; Cole, D.E.; Gundberg, C.M. Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol. Rev., 1989, 69(3), 990-1047.
[http://dx.doi.org/10.1152/physrev.1989.69.3.990] [PMID: 2664828]
[10]
Ducy, P.; Geoffroy, V.; Karsenty, G. Study of osteoblast-specific expression of one mouse osteocalcin gene: Characterization of the factor binding to OSE2. Connect. Tissue Res., 1996, 35(1-4), 7-14.
[http://dx.doi.org/10.3109/03008209609029169] [PMID: 9084638]
[11]
Dowd, T.L.; Rosen, J.F.; Li, L.; Gundberg, C.M. The three-dimensional structure of bovine calcium ion-bound osteocalcin using 1H NMR spectroscopy. Biochemistry, 2003, 42(25), 7769-7779.
[http://dx.doi.org/10.1021/bi034470s] [PMID: 12820886]
[12]
Hoang, Q.Q.; Sicheri, F.; Howard, A.J.; Yang, D.S.C. Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature, 2003, 425(6961), 977-980.
[http://dx.doi.org/10.1038/nature02079] [PMID: 14586470]
[13]
Puchacz, E.; Lian, J.B.; Stein, G.S.; Wozney, J.; Huebner, K.; Croce, C. Chromosomal localization of the human osteocalcin gene. Endocrinology, 1989, 124(5), 2648-2650.
[http://dx.doi.org/10.1210/endo-124-5-2648] [PMID: 2785029]
[14]
Lacombe, J.; Al Rifai, O.; Loter, L.; Moran, T.; Turcotte, A.F.; Grenier-Larouche, T.; Tchernof, A.; Biertho, L.; Carpentier, A.C.; Prud’homme, D.; Rabasa-Lhoret, R.; Karsenty, G.; Gagnon, C.; Jiang, W.; Ferron, M. Measurement of bioactive osteocalcin in humans using a novel immunoassay reveals association with glucose metabolism and β-cell function. Am. J. Physiol. Endocrinol. Metab., 2020, 318(3), E381-E391.
[http://dx.doi.org/10.1152/ajpendo.00321.2019] [PMID: 31935114]
[15]
Houben, R.J.; Jin, D.; Stafford, D.W.; Proost, P.; Ebberink, R.H.; Vermeer, C.; Soute, B.A. Osteocalcin binds tightly to the gamma-glutamylcarboxylase at a site distinct from that of the other known vitamin K-dependent proteins. Biochem. J., 1999, 341(Pt 2), 265-269.
[http://dx.doi.org/10.1042/bj3410265] [PMID: 10393081]
[16]
Morris, D.P.; Stevens, R.D.; Wright, D.J.; Stafford, D.W. Processive post-translational modification. Vitamin K-dependent carboxylation of a peptide substrate. J. Biol. Chem., 1995, 270(51), 30491-30498.
[http://dx.doi.org/10.1074/jbc.270.51.30491] [PMID: 8530480]
[17]
Brown, J.P.; Delmas, P.D.; Malaval, L.; Edouard, C.; Chapuy, M.C.; Meunier, P.J. Serum bone Gla-protein: A specific marker for bone formation in postmenopausal osteoporosis. Lancet, 1984, 1(8386), 1091-1093.
[http://dx.doi.org/10.1016/S0140-6736(84)92506-6] [PMID: 6144827]
[18]
Looker, A.C.; Bauer, D.C.; Chesnut, C.H. 3rd.; Gundberg, C.M.; Hochberg, M.C.; Klee, G.; Kleerekoper, M.; Watts, N.B.; Bell, N.H. Clinical use of biochemical markers of bone remodeling: Current status and future directions. Osteop Int., 2000, 11, 467-480.
[http://dx.doi.org/10.1007/s001980070088]
[19]
Ducy, P.; Desbois, C.; Boyce, B.; Pinero, G.; Story, B.; Dunstan, C.; Smith, E.; Bonadio, J.; Goldstein, S.; Gundberg, C.; Bradley, A.; Karsenty, G. Increased bone formation in osteocalcin-deficient mice. Nature, 1996, 382(6590), 448-452.
[http://dx.doi.org/10.1038/382448a0] [PMID: 8684484]
[20]
Lee, N.K.; Sowa, H.; Hinoi, E.; Ferron, M.; Ahn, J.D.; Confavreux, C.; Dacquin, R.; Mee, P.J.; McKee, M.D.; Jung, D.Y.; Zhang, Z.; Kim, J.K.; Mauvais-Jarvis, F.; Ducy, P.; Karsenty, G. Endocrine regulation of energy metabolism by the skeleton. Cell, 2007, 130(3), 456-469.
[http://dx.doi.org/10.1016/j.cell.2007.05.047] [PMID: 17693256]
[21]
Oury, F.; Sumara, G.; Sumara, O.; Ferron, M.; Chang, H.; Smith, C.E.; Hermo, L.; Suarez, S.; Roth, B.L.; Ducy, P.; Karsenty, G. Endocrine regulation of male fertility by the skeleton. Cell, 2011, 144(5), 796-809.
[http://dx.doi.org/10.1016/j.cell.2011.02.004] [PMID: 21333348]
[22]
Oury, F.; Khrimian, L.; Denny, C.A.; Gardin, A.; Chamouni, A.; Goeden, N.; Huang, Y.Y.; Lee, H.; Srinivas, P.; Gao, X.B.; Suyama, S.; Langer, T.; Mann, J.J.; Horvath, T.L.; Bonnin, A.; Karsenty, G. Maternal and offspring pools of osteocalcin influence brain development and functions. Cell, 2013, 155(1), 228-241.
[http://dx.doi.org/10.1016/j.cell.2013.08.042] [PMID: 24074871]
[23]
Gundberg, C.M.; Nieman, S.D.; Abrams, S.; Rosen, H. Vitamin K status and bone health: An analysis of methods for determination of undercarboxylated osteocalcin. J. Clin. Endocrinol. Metab., 1998, 83(9), 3258-3266.
[http://dx.doi.org/10.1210/jc.83.9.3258] [PMID: 9745439]
[24]
Cairns, J.R.; Price, P.A. Direct demonstration that the vitamin K-dependent bone Gla protein is incompletely gamma-carboxylated in humans. J. Bone Miner. Res., 1994, 9(12), 1989-1997.
[http://dx.doi.org/10.1002/jbmr.5650091220] [PMID: 7872066]
[25]
Ferron, M.; Wei, J.; Yoshizawa, T.; Del Fattore, A.; DePinho, R.A.; Teti, A.; Ducy, P.; Karsenty, G. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell, 2010, 142(2), 296-308.
[http://dx.doi.org/10.1016/j.cell.2010.06.003] [PMID: 20655470]
[26]
Nagy, V.; Penninger, J.M. The RANKL-RANK Story. Gerontology, 2015, 61(6), 534-542.
[http://dx.doi.org/10.1159/000371845] [PMID: 25720990]
[27]
Cristiani, A.; Maset, F.; De Toni, L.; Guidolin, D.; Sabbadin, D.; Strapazzon, G.; Moro, S.; De Filippis, V.; Foresta, C. Carboxylation-dependent conformational changes of human osteocalcin. Front. Biosci., 2014, 19, 1105-1116.
[http://dx.doi.org/10.2741/4270] [PMID: 24896339]
[28]
Pi, M.; Faber, P.; Ekema, G.; Jackson, P.D.; Ting, A.; Wang, N.; Fontilla-Poole, M.; Mays, R.W.; Brunden, K.R.; Harrington, J.J.; Quarles, L.D. Identification of a novel extracellular cation-sensing G-protein-coupled receptor. J. Biol. Chem., 2005, 280(48), 40201-40209.
[http://dx.doi.org/10.1074/jbc.M505186200] [PMID: 16199532]
[29]
Wellendorph, P.; Bräuner-Osborne, H. Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor. Gene, 2004, 335, 37-46.
[http://dx.doi.org/10.1016/j.gene.2004.03.003] [PMID: 15194188]
[30]
Wei, J.; Hanna, T.; Suda, N.; Karsenty, G.; Ducy, P. Osteocalcin promotes β-cell proliferation during development and adulthood through GPRC6A. Diabetes, 2014, 63(3), 1021-1031.
[http://dx.doi.org/10.2337/db13-0887] [PMID: 24009262]
[31]
Pi, M.; Kapoor, K.; Ye, R.; Nishimoto, S.K.; Smith, J.C.; Baudry, J.; Quarles, L.D. Evidence for osteocalcin binding and activation of GPRC6A in β-Cells. Endocrinology, 2016, 157(5), 1866-1880.
[http://dx.doi.org/10.1210/en.2015-2010] [PMID: 27007074]
[32]
Mizokami, A.; Yasutake, Y.; Gao, J.; Matsuda, M.; Takahashi, I.; Takeuchi, H.; Hirata, M. Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice. PLoS One, 2013, 8(2), e57375.
[http://dx.doi.org/10.1371/journal.pone.0057375] [PMID: 23437377]
[33]
Otani, T.; Mizokami, A.; Hayashi, Y.; Gao, J.; Mori, Y.; Nakamura, S.; Takeuchi, H.; Hirata, M. Signaling pathway for adiponectin expression in adipocytes by osteocalcin. Cell. Signal., 2015, 27(3), 532-544.
[http://dx.doi.org/10.1016/j.cellsig.2014.12.018] [PMID: 25562427]
[34]
Ferron, M.; Hinoi, E.; Karsenty, G.; Ducy, P. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc. Natl. Acad. Sci. USA, 2008, 105(13), 5266-5270.
[http://dx.doi.org/10.1073/pnas.0711119105] [PMID: 18362359]
[35]
Du, J.; Zhang, M.; Lu, J.; Zhang, X.; Xiong, Q.; Xu, Y.; Bao, Y.; Jia, W. Osteocalcin improves nonalcoholic fatty liver disease in mice through activation of Nrf2 and inhibition of JNK. Endocrine, 2016, 53(3), 701-709.
[http://dx.doi.org/10.1007/s12020-016-0926-5] [PMID: 26994931]
[36]
Liu, S.; Gao, F.; Wen, L.; Ouyang, M.; Wang, Y.; Wang, Q.; Luo, L.; Jian, Z. Osteocalcin induces proliferation via positive activation of the PI3K/Akt, P38 MAPK pathways and promotes differentiation through activation of the GPRC6A-ERK1/2 pathway in C2C12 myoblast cells. Cell. Physiol. Biochem., 2017, 43(3), 1100-1112.
[http://dx.doi.org/10.1159/000481752] [PMID: 28977794]
[37]
Mera, P.; Laue, K.; Wei, J.; Berger, J.M.; Karsenty, G. Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Mol. Metab., 2016, 5(10), 1042-1047.
[http://dx.doi.org/10.1016/j.molmet.2016.07.002] [PMID: 27689017]
[38]
Karsenty, G.; Mera, P. Molecular bases of the crosstalk between bone and muscle. Bone, 2018, 115, 43-49.
[http://dx.doi.org/10.1016/j.bone.2017.04.006] [PMID: 28428077]
[39]
De Toni, L.; De Filippis, V.; Tescari, S.; Ferigo, M.; Ferlin, A.; Scattolini, V.; Avogaro, A.; Vettor, R.; Foresta, C. Uncarboxylated osteocalcin stimulates 25-hydroxy vitamin D production in Leydig cell line through a GPRC6a-dependent pathway. Endocrinology, 2014, 155(11), 4266-4274.
[http://dx.doi.org/10.1210/en.2014-1283] [PMID: 25093461]
[40]
Coskun, G.; Sencar, L.; Tuli, A.; Saker, D.; Alparslan, M.M.; Polat, S. Effects of osteocalcin on synthesis of testosterone and INSL3 during adult leydig cell differentiation. Int. J. Endocrinol., 2019, 2019, 1041760.
[http://dx.doi.org/10.1155/2019/1041760] [PMID: 31558901]
[41]
Amrein, K.; Scherkl, M.; Hoffmann, M.; Neuwersch-Sommeregger, S.; Köstenberger, M.; Tmava Berisha, A.; Martucci, G.; Pilz, S.; Malle, O. Vitamin D deficiency 2.0: an update on the current status worldwide. Eur. J. Clin. Nutr., 2020, 74(11), 1493-1513.
[http://dx.doi.org/10.1038/s41430-020-0558-y] [PMID: 31959942]
[42]
Pilz, S.; Verheyen, N.; Grübler, M.R.; Tomaschitz, A.; März, W. Vitamin D and cardiovascular disease prevention. Nat. Rev. Cardiol., 2016, 13(7), 404-417.
[http://dx.doi.org/10.1038/nrcardio.2016.73] [PMID: 27150190]
[43]
Ferlin, A.; De Toni, L.; Sandri, M.; Foresta, C. Relaxin and insulin-like peptide 3 in the musculoskeletal system: From bench to bedside. Br. J. Pharmacol., 2017, 174(10), 1015-1024.
[http://dx.doi.org/10.1111/bph.13490] [PMID: 27059798]
[44]
De Toni, L.; Agoulnik, A.I.; Sandri, M.; Foresta, C.; Ferlin, A. INSL3 in the muscolo-skeletal system. Mol. Cell. Endocrinol., 2019, 487, 12-17.
[http://dx.doi.org/10.1016/j.mce.2018.12.021] [PMID: 30625346]
[45]
Ferlin, A.; Perilli, L.; Gianesello, L.; Taglialavoro, G.; Foresta, C. Profiling insulin like factor 3 (INSL3) signaling in human osteoblasts. PLoS One, 2011, 6(12), e29733.
[http://dx.doi.org/10.1371/journal.pone.0029733] [PMID: 22216350]
[46]
Overvad, S.; Bay, K.; Bojesen, A.; Gravholt, C.H. Low INSL3 in Klinefelter syndrome is related to osteocalcin, testosterone treatment and body composition, as well as measures of the hypothalamic-pituitary-gonadal axis. Andrology, 2014, 2(3), 421-427.
[http://dx.doi.org/10.1111/j.2047-2927.2014.00204.x] [PMID: 24659579]
[47]
Olmedillas, H.; Gonzalez-Agüero, A.; Rapún-López, M.; Gracia-Marco, L.; Gomez-Cabello, A.; Pradas de la Fuente, F.; Moreno, L.A.; Casajús, J.A.; Vicente-Rodríguez, G. Bone metabolism markers and vitamin D in adolescent cyclists. Arch. Osteoporos., 2018, 13(1), 11.
[http://dx.doi.org/10.1007/s11657-018-0415-y] [PMID: 29397487]
[48]
van de Peppel, J.; van Leeuwen, J.P. Vitamin D and gene networks in human osteoblasts. Front. Physiol., 2014, 5, 137.
[http://dx.doi.org/10.3389/fphys.2014.00137] [PMID: 24782782]
[49]
De Toni, L.; Di Nisio, A.; Rocca, M.S.; De Rocco Ponce, M.; Ferlin, A.; Foresta, C. Osteocalcin, a bone-derived hormone with important andrological implications. Andrology, 2017, 5(4), 664-670.
[http://dx.doi.org/10.1111/andr.12359] [PMID: 28395130]
[50]
Mizokami, A.; Wang, D.; Tanaka, M.; Gao, J.; Takeuchi, H.; Matsui, T.; Hirata, M. An extract from pork bones containing osteocalcin improves glucose metabolism in mice by oral administration. Biosci. Biotechnol. Biochem., 2016, 80(11), 2176-2183.
[http://dx.doi.org/10.1080/09168451.2016.1214530] [PMID: 27460506]
[51]
Mizokami, A.; Mukai, S.; Gao, J.; Kawakubo-Yasukochi, T.; Otani, T.; Takeuchi, H.; Jimi, E.; Hirata, M. GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin. J. Endocrinol., 2020, 244(2), 285-296.
[http://dx.doi.org/10.1530/JOE-19-0288] [PMID: 31693486]
[52]
Zhou, B.; Li, H.; Liu, J.; Xu, L.; Guo, Q.; Zang, W.; Sun, H.; Wu, S. Autophagic dysfunction is improved by intermittent administration of osteocalcin in obese mice. Int. J. Obes., 2016, 40(5), 833-843.
[http://dx.doi.org/10.1038/ijo.2016.1] [PMID: 26740123]
[53]
Pi, M.; Kapoor, K.; Ye, R.; Hwang, D.J.; Miller, D.D.; Smith, J.C.; Baudry, J.; Quarles, L.D. Computationally identified novel agonists for GPRC6A. PLoS One, 2018, 13(4), e0195980.
[http://dx.doi.org/10.1371/journal.pone.0195980] [PMID: 29684031]
[54]
Pi, M.; Kapoor, K.; Ye, R.; Smith, J.C.; Baudry, J.; Quarles, L.D. GPCR6A is a molecular target for the natural products gallate and EGCG in green tea. Mol. Nutr. Food Res., 2018, 62(8), e1700770.
[http://dx.doi.org/10.1002/mnfr.201700770] [PMID: 29468843]
[55]
Pi, M.; Parrill, A.L.; Quarles, L.D. GPRC6A mediates the non-genomic effects of steroids. J. Biol. Chem., 2010, 285(51), 39953-39964.
[http://dx.doi.org/10.1074/jbc.M110.158063] [PMID: 20947496]
[56]
De Toni, L.; Guidolin, D.; De Filippis, V.; Tescari, S.; Strapazzon, G.; Santa Rocca, M.; Ferlin, A.; Plebani, M.; Foresta, C. Osteocalcin and sex hormone binding globulin compete on a specific binding site of GPRC6A. Endocrinology, 2016, 157(11), 4473-4486.
[http://dx.doi.org/10.1210/en.2016-1312] [PMID: 27673554]
[57]
De Toni, L.; Guidolin, D.; De Filippis, V.; Peterle, D.; Rocca, M.S.; Di Nisio, A.; De Rocco Ponce, M.; Foresta, C. SHBG141-161 domain-peptide stimulates GPRC6A-mediated response in leydig and β-Langerhans cell lines. Sci. Rep., 2019, 9(1), 19432.
[http://dx.doi.org/10.1038/s41598-019-55941-x] [PMID: 31857654]
[58]
Qaradakhi, T.; Gadanec, L.K.; Tacey, A.B.; Hare, D.L.; Buxton, B.F.; Apostolopoulos, V.; Levinger, I.; Zulli, A. The effect of recombinant undercarboxylated osteocalcin on endothelial dysfunction. Calcif. Tissue Int., 2019, 105(5), 546-556.
[http://dx.doi.org/10.1007/s00223-019-00600-6] [PMID: 31485687]
[59]
Yi, M.; Wu, Y.; Long, J.; Liu, F.; Liu, Z.; Zhang, Y.H.; Sun, X.P.; Fan, Z.X.; Gao, J.; Si, J.; Zuo, X.B.; Zhang, L.M.; Shi, N.; Miao, Z.P.; Bai, Z.R.; Liu, B.Y.; Liu, H.R.; Li, J. Exosomes secreted from osteocalcin-overexpressing endothelial progenitor cells promote endothelial cell angiogenesis. Am. J. Physiol. Cell Physiol., 2019, 317(5), C932-C941.
[http://dx.doi.org/10.1152/ajpcell.00534.2018] [PMID: 31411920]
[60]
Yeap, B.B.; Alfonso, H.; Chubb, S.A.; Gauci, R.; Byrnes, E.; Beilby, J.P.; Ebeling, P.R.; Handelsman, D.J.; Allan, C.A.; Grossmann, M.; Norman, P.E.; Flicker, L. Higher serum undercarboxylated osteocalcin and other bone turnover markers are associated with reduced diabetes risk and lower estradiol concentrations in older men. J. Clin. Endocrinol. Metab., 2015, 100(1), 63-71.
[http://dx.doi.org/10.1210/jc.2014-3019] [PMID: 25365314]
[61]
Martinez-Portilla, R.J.; Villafan-Bernal, J.R.; Lip-Sosa, D.L.; Meler, E.; Clotet, J.; Serna-Vela, F.J.; Velazquez-Garcia, S.; Serrano-Diaz, L.C.; Figueras, F. Osteocalcin serum levels in gestational diabetes mellitus and their intrinsic and extrinsic determinants: Systematic review and meta-analysis. J. Diabetes Res., 2018, 2018, 4986735.
[http://dx.doi.org/10.1155/2018/4986735] [PMID: 30693288]
[62]
Pi, M.; Nishimoto, S.K.; Quarles, L.D. GPRC6A: Jack of all metabolism (or master of none). Mol. Metab., 2016, 6(2), 185-193.
[http://dx.doi.org/10.1016/j.molmet.2016.12.006] [PMID: 28180060]
[63]
Kindblom, J.M.; Ohlsson, C.; Ljunggren, O.; Karlsson, M.K.; Tivesten, A.; Smith, U.; Mellström, D. Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J. Bone Miner. Res., 2009, 24(5), 785-791.
[http://dx.doi.org/10.1359/jbmr.081234] [PMID: 19063687]
[64]
Kanazawa, I.; Yamaguchi, T.; Yamamoto, M.; Yamauchi, M.; Kurioka, S.; Yano, S.; Sugimoto, T. Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. J. Clin. Endocrinol. Metab., 2009, 94(1), 45-49.
[http://dx.doi.org/10.1210/jc.2008-1455] [PMID: 18984661]
[65]
Pittas, A.G.; Harris, S.S.; Eliades, M.; Stark, P.; Dawson-Hughes, B. Association between serum osteocalcin and markers of metabolic phenotype. J. Clin. Endocrinol. Metab., 2009, 94(3), 827-832.
[http://dx.doi.org/10.1210/jc.2008-1422] [PMID: 19088165]
[66]
Saleem, U.; Mosley, T.H., Jr; Kullo, I.J. Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arterioscler. Thromb. Vasc. Biol., 2010, 30(7), 1474-1478.
[http://dx.doi.org/10.1161/ATVBAHA.110.204859] [PMID: 20395593]
[67]
Yeap, B.B.; Chubb, S.A.; Flicker, L.; McCaul, K.A.; Ebeling, P.R.; Beilby, J.P.; Norman, P.E. Reduced serum total osteocalcin is associated with metabolic syndrome in older men via waist circumference, hyperglycemia, and triglyceride levels. Eur. J. Endocrinol., 2010, 163(2), 265-272.
[http://dx.doi.org/10.1530/EJE-10-0414] [PMID: 20501596]
[68]
Khrimian, L.; Obri, A.; Ramos-Brossier, M.; Rousseaud, A.; Moriceau, S.; Nicot, A.S.; Mera, P.; Kosmidis, S.; Karnavas, T.; Saudou, F.; Gao, X.B.; Oury, F.; Kandel, E.; Karsenty, G. Gpr158 mediates osteocalcin’s regulation of cognition. J. Exp. Med., 2017, 214(10), 2859-2873.
[http://dx.doi.org/10.1084/jem.20171320] [PMID: 28851741]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 27
ISSUE: 12
Year: 2020
Published on: 05 May, 2020
Page: [1268 - 1275]
Pages: 8
DOI: 10.2174/0929866527666200505220459
Price: $65

Article Metrics

PDF: 30
HTML: 1