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RS 2247911 polymorphism of GPRC6A gene and serum undercarboxylated-osteocalcin are associated with testis function

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Abstract

Purpose

Undercarboxylated-Osteocalcin (ucOCN), acting on its putative receptor GPRC6A, was shown to stimulate testosterone (T) production by Leydig cells in rodents, in parallel with the hypothalamus-pituitary–gonadal axis (HPG) mediated by luteinizing hormone (LH). The aim of this cross-sectional study was to evaluate the association among serum ucOCN, rs2247911 polymorphism of GPRC6A gene and the endocrine/semen pattern in a cohort of infertile males, possibly identifying an involvement of the ucOCN-GPRC6A axis on testis function.

Methods

190 males, including 74 oligozoospermic subjects, 58 azoosperminc patients and 58 normozoospermic controls, were prospectively recruited at the Orient Hospital for Infertility, Assisted Reproduction and Genetics in Syria (Study N. 18FP), from July 2018 to June 2020. Outpatient evaluation included the clinical history, anthropometrics and a fasting blood sampling for hormonals, serum OCN (both carboxylated and undercarboxylated), glycemic and lipid profile and screening for rs2247911 GPRC6A gene polymorphism.

Results

Higher serum ucOCN associated with higher T and HDL-cholesterol (respectively: r = 0.309, P < 0.001 and r = 0.248, P = 0.001), and with lower FSH (r =  – 0.327, P < 0.001) and LDL-cholesterol (r =  – 0.171; P = 0.018). Patients bearing the GG genotype of rs2247911 had higher sperm count compared to GA genotype (P = 0.043) and, compared to both AG and AA genotypes, had higher serum T (P = 0.004, P = 0.001) and lower triglycerides levels (P = 0.002, P < 0.001). Upon normalization for LH levels and body mass index, rs2274911 and ucOCN were significantly associated with higher serum T at linear stepwise regression analysis (P = 0.013, P = 0.007).

Conclusions

Our data suggest the involvement of ucOCN-GPRC6A axis in the regulation of T production by the testis, subsidiary to HPG.

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References

  1. Kaprara A, Huhtaniemi IT (2018) The hypothalamus-pituitary-gonad axis: Tales of mice and men. Metabolism: clinical and experimental 86:3–17. https://doi.org/10.1016/J.METABOL.2017.11.018

  2. Karsenty G (2017) Update on the biology of osteocalcin. Endocr Pract 23:1270–1274. https://doi.org/10.4158/EP171966.RA

    Article  PubMed  Google Scholar 

  3. Hauschka PV, Lian JB, Cole DE, Gundberg CM (1989) Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69:990–1047. https://doi.org/10.1152/PHYSREV.1989.69.3.990

    Article  CAS  PubMed  Google Scholar 

  4. Price PA (1985) Vitamin K-dependent formation of bone gla protein (Osteocalcin) and its function. Vitam Horm 42:65–108. https://doi.org/10.1016/S0083-6729(08)60061-8

    Article  CAS  PubMed  Google Scholar 

  5. Ducy P, Desbois C, Boyce B et al (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382:448–452. https://doi.org/10.1038/382448a0

    Article  CAS  PubMed  Google Scholar 

  6. Cristiani A, Maset F, De Toni L et al (2014) Carboxylation-dependent conformational changes of human osteocalcin. Front Biosci 19:1105–1116. https://doi.org/10.2741/4270

    Article  CAS  Google Scholar 

  7. Wei J, Karsenty G (2015) An overview of the metabolic functions of osteocalcin. Rev Endocr Metab Disord 16:93–98. https://doi.org/10.1007/S11154-014-9307-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ferron M, Wei J, Yoshizawa T et al (2010) Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142:296–308. https://doi.org/10.1016/j.cell.2010.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Foresta C, Strapazzon G, De Toni L et al (2011) Androgens modulate osteocalcin release by human visceral adipose tissue. Clin Endocrinol 75:64–69. https://doi.org/10.1111/j.1365-2265.2011.03997.x

    Article  CAS  Google Scholar 

  10. Wei J, Hanna T, Suda N et al (2014) Osteocalcin promotes β-cell proliferation during development and adulthood through Gprc6a. Diabetes 63:1021–1031. https://doi.org/10.2337/db13-0887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shahrour HE, Al Fahom S, Al-Massarani G et al (2022) Osteocalcin-expressing endothelial progenitor cells and serum osteocalcin forms are independent biomarkers of coronary atherosclerotic disease severity in male and female patients. J Endocrinol Invest. https://doi.org/10.1007/S40618-022-01744-3

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ferron M, Hinoi E, Karsenty G, Ducy P (2008) Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci USA 105:5266–5270. https://doi.org/10.1073/pnas.0711119105

    Article  PubMed  PubMed Central  Google Scholar 

  13. Karsenty G, Mera P (2018) Molecular bases of the crosstalk between bone and muscle. Bone 115:43–49. https://doi.org/10.1016/j.bone.2017.04.006

    Article  CAS  PubMed  Google Scholar 

  14. Karsenty G (2012) The mutual dependence between bone and gonads. J Endocrinol 213:107–114. https://doi.org/10.1530/JOE-11-0452

    Article  CAS  PubMed  Google Scholar 

  15. Pi M, Quarles LD (2012) Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks. Endocrinology 153:2062–2069. https://doi.org/10.1210/EN.2011-2117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Khrimian L, Obri A, Ramos-Brossier M et al (2017) Gpr158 mediates osteocalcin’s regulation of cognition. J Exp Med. https://doi.org/10.1084/jem.20171320

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lee NK, Sowa H, Hinoi E et al (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469. https://doi.org/10.1016/j.cell.2007.05.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Oury F, Sumara G, Sumara O et al (2011) Endocrine regulation of male fertility by the skeleton. Cell 144:796–809. https://doi.org/10.1016/j.cell.2011.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pi M, Chen L, Huang MZ et al (2008) GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. PLoS ONE. https://doi.org/10.1371/journal.pone.0003858

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ferron M, Lacombe J (2014) Regulation of energy metabolism by the skeleton: osteocalcin and beyond. Arch Biochem Biophys 561:137–146. https://doi.org/10.1016/J.ABB.2014.05.022

    Article  CAS  PubMed  Google Scholar 

  21. Oury F, Ferron M, Huizhen W et al (2013) Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. J Clin Investig 123:2421–2433. https://doi.org/10.1172/JCI65952.insulin

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Haiman CA, Han Y, Feng Y et al (2013) Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. PLoS Genet 9:e1003419. https://doi.org/10.1371/journal.pgen.1003419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. De Toni L, Di Nisio A, Rocca MS et al (2017) Osteocalcin, a bone-derived hormone with important andrological implications. Andrology 5:664–670. https://doi.org/10.1111/ANDR.12359

    Article  PubMed  Google Scholar 

  24. Sarah M Paksima, Hala N Madanat, Steven R Hawks (2002) A contextual model for reproductive health education: fertility and family planning in Jordan - PubMed. In: Promot Edu. https://pubmed.ncbi.nlm.nih.gov/12426969/. Accessed 4 Mar 2022

  25. (2014) WHO | Infecundity, infertility, and childlessness in developing countries. Demographic and Health Surveys (DHS) Comparative reports No. 9. WHO

  26. Garolla A, Grande G, Palego P et al (2021) Central role of ultrasound in the evaluation of testicular function and genital tract obstruction in infertile males. Andrology 9:1490–1498. https://doi.org/10.1111/ANDR.13060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. (2010) WHO laboratory manual for the Examination and processing of human semen FIFTH EDITION

  28. Hosker JP, Matthews DR, Rudenski AS et al (1985) Continuous infusion of glucose with model assessment: measurement of insulin resistance and β-cell function in man. Diabetologia 28:401–411. https://doi.org/10.1007/BF00280882

    Article  CAS  PubMed  Google Scholar 

  29. Di Nisio A, Rocca MS, Fadini GP et al (2017) The rs2274911 polymorphism in GPRC6A gene is associated with insulin resistance in normal weight and obese subjects. Clin Endocrinol 86:185–191. https://doi.org/10.1111/cen.13248

    Article  CAS  Google Scholar 

  30. Karsenty G, Oury F (2014) Regulation of male fertility by the bone-derived hormone osteocalcin. Mol Cell Endocrinol 382:521–526. https://doi.org/10.1016/J.MCE.2013.10.008

    Article  CAS  PubMed  Google Scholar 

  31. Oury F (2012) A crosstalk between bone and gonads. Ann N Y Acad Sci 1260:1–7. https://doi.org/10.1111/J.1749-6632.2011.06360.X

    Article  CAS  PubMed  Google Scholar 

  32. Diegel CR, Hann S, Ayturk UM et al (2020) An osteocalcin-deficient mouse strain without endocrine abnormalities. PLoS Genet 16:e1008361. https://doi.org/10.1371/JOURNAL.PGEN.1008361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lin X, Hanson E, Betik AC et al (2016) Hindlimb Immobilization, But Not Castration, Induces Reduction of Undercarboxylated Osteocalcin Associated With Muscle Atrophy in Rats. J Bone Miner Res 31:1967–1978. https://doi.org/10.1002/JBMR.2884

    Article  CAS  PubMed  Google Scholar 

  34. Karsenty G, Oury F (2014) Molecular and Cellular Endocrinology Regulation of male fertility by the bone-derived hormone osteocalcin. Mol Cell Endocrinol 382:521–526. https://doi.org/10.1016/j.mce.2013.10.008

    Article  CAS  PubMed  Google Scholar 

  35. Agas D, Lacava G, Sabbieti MG (2018) Bone and bone marrow disruption by endocrine-active substances. J Cell Physiol 234:192–213. https://doi.org/10.1002/JCP.26837

    Article  PubMed  Google Scholar 

  36. Kirmani S, Atkinson EJ, Melton LJ et al (2011) Relationship of testosterone and osteocalcin levels during growth. J Bone Miner Res 26:2212–2216. https://doi.org/10.1002/jbmr.421

    Article  CAS  PubMed  Google Scholar 

  37. Hiam D, Landen S, Jacques M et al (2021) Osteocalcin and its forms respond similarly to exercise in males and females. Bone. https://doi.org/10.1016/J.BONE.2020.115818

    Article  PubMed  Google Scholar 

  38. Kanazawa I, Tanaka K, Ogawa N et al (2013) Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus. Osteoporos Int 24:1115–1119. https://doi.org/10.1007/s00198-012-2017-7

    Article  CAS  PubMed  Google Scholar 

  39. Yang Y, Zheng S, Wang W et al (2019) Osteocalcin levels in male idiopathic hypogonadotropic hypogonadism: relationship with the testosterone secretion and metabolic profiles. Front Endocrin 10:1–7. https://doi.org/10.3389/fendo.2019.00687

    Article  Google Scholar 

  40. De Toni L, De Nisio A, Speltra E et al (2016) Polymorphism rs2274911 of GPRC6A as a novel risk factor for testis failure. J Clin Endocrinol Metabol 101:953–961. https://doi.org/10.1210/jc.2015-3967

    Article  CAS  Google Scholar 

  41. Skakkebæk NE, Lindahl-Jacobsen R, Levine H et al (2022) Environmental factors in declining human fertility. Nat Rev Endocrinol 18:139–157. https://doi.org/10.1038/S41574-021-00598-8

    Article  PubMed  Google Scholar 

  42. De Toni L, Jawich K, De Rocco PM et al (2020) Osteocalcin: a protein hormone connecting metabolism, bone and testis function. Protein Pept Lett 27:1268–1275. https://doi.org/10.2174/0929866527666200505220459

    Article  CAS  PubMed  Google Scholar 

  43. Sharma R, Biedenharn KR, Fedor JM, Agarwal A (2013) Lifestyle factors and reproductive health: Taking control of your fertility. Reprod Biol Endocrinol 11:1–15. https://doi.org/10.1186/1477-7827-11-66/TABLES/1

    Article  Google Scholar 

  44. Syria crisis. https://www.who.int/emergencies/situations/syria-crisis. Accessed 2 Jul 2021

  45. Yeap BB, Alfonso H, Paul Chubb SA et al (2015) 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 100:63–71. https://doi.org/10.1210/JC.2014-3019

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Khaled Albaghdadi, Dr. Nemah ALsayed Jameel and Farah Brangakgi for their assistance in data collection.

Funding

This study received the support of the University Cooperation Initiatives, University of Padova, Italy and the Scientific Research Support Fund, Ministry of Higher Education and Scientific Research, Syrian Arab Republic.

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Author notes

  1. Kenda Jawich and Maria Santa Rocca equally contributed to the manuscript.

Authors and Affiliations

  1. Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syrian Arab Republic

    K. Jawich & S. Al Fahoum

  2. Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padua, Italy

    M. Santa Rocca, A. Di Nisio, C. Foresta, A. Ferlin & L. De Toni

  3. Department of Embryology and Reproductive Medicine, Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic

    M. Alhalabi

  4. Unit of Andrology and Reproductive Medicine, University Hospital of Padova, Padua, Italy

    M. Santa Rocca

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  1. K. Jawich
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Contributions

K.J. and M.S.R. were responsible for data collection. Data management was performed by K.J., M.S.R. and L.D.T. All authors contributed to the study conception and design. A.D.N. performed the statistical analyses. K.J., S.A.F., M.A., A.F. and L.D.T. drafted the manuscript. C.F. supervised manuscript concept and design. All authors took part in the revision of the manuscript and approved the final version for publication.

Corresponding author

Correspondence to S. Al Fahoum.

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The authors have no conflict of interest to disclose.

Ethical approval

The study was approved by the Ethics Committee of Damascus University (protocol number N.18FP,2018).

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All procedures in this study were performed in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and subsequent amendments or comparable ethical standards.

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Appropriate informed consent was acquired from all participants.

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Jawich, K., Rocca, M.S., Al Fahoum, S. et al. RS 2247911 polymorphism of GPRC6A gene and serum undercarboxylated-osteocalcin are associated with testis function. J Endocrinol Invest 45, 1673–1682 (2022). https://doi.org/10.1007/s40618-022-01803-9

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