Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis
Franck Oury, … , Ingrid Plotton, Gerard Karsenty
Franck Oury, … , Ingrid Plotton, Gerard Karsenty
Published May 24, 2013
Citation Information: J Clin Invest. 2013;123(6):2421-2433. https://doi.org/10.1172/JCI65952.
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Research Article

Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis

Abstract

The osteoblast-derived hormone osteocalcin promotes testosterone biosynthesis in the mouse testis by binding to GPRC6A in Leydig cells. Interestingly, Osteocalcin-deficient mice exhibit increased levels of luteinizing hormone (LH), a pituitary hormone that regulates sex steroid synthesis in the testes. These observations raise the question of whether LH regulates osteocalcin’s reproductive effects. Additionally, there is growing evidence that osteocalcin levels are a reliable marker of insulin secretion and sensitivity and circulating levels of testosterone in humans, but the endocrine function of osteocalcin is unclear. Using mouse models, we found that osteocalcin and LH act in 2 parallel pathways and that osteocalcin-stimulated testosterone synthesis is positively regulated by bone resorption and insulin signaling in osteoblasts. To determine the importance of osteocalcin in humans, we analyzed a cohort of patients with primary testicular failure and identified 2 individuals harboring the same heterozygous missense variant in one of the transmembrane domains of GPRC6A, which prevented the receptor from localizing to the cell membrane. This study uncovers the existence of a second endocrine axis that is necessary for optimal male fertility in the mouse and suggests that osteocalcin modulates reproductive function in humans.

Authors

Franck Oury, Mathieu Ferron, Wang Huizhen, Cyrille Confavreux, Lin Xu, Julie Lacombe, Prashanth Srinivas, Alexandre Chamouni, Francesca Lugani, Herve Lejeune, T. Rajendra Kumar, Ingrid Plotton, Gerard Karsenty

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Figure 1

Analysis of the rescue of male fertility phenotype in Lhb–/– male mice after osteocalcin injections.

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Analysis of the rescue of male fertility phenotype in Lhb–/– male mice a...
(A) Measurement of the uncarboxylated (GLU-OCN), carboxylated (GLA13-OCN), total (total-OCN), and undercarboxylated (GLU13-OCN) forms of osteocalcin in the serum of 10-week-old Lh-deficient mice (Lhb–/–) (n = 7) versus WT (n = 5). (B) Circulating testosterone levels in 12-week-old WT (n = 5) and Lhb–/– (n = 7) mice and in Lhb–/– mice injected for 1 month with PBS (n = 8) or osteocalcin (3 ng/ml) (n = 5). (C and D) Testes cross-sections of WT and Lhb–/– injected for 1 month with PBS, osteocalcin (3 ng/g/d) or hCG (5 UI twice a week). (C) Histological demonstration of the interstitial tissue hypoplasia (2 first rows) and of the absence of spermatogenesis (2 last rows) observed in Lhb–/– mice. While injections of hCG rescue the phenotype, PBS or osteocalcin do not. The black line delimits the frame zoom shown in the second row. The head arrows point to the interstitial tissue containing Leydig cells. Rsp, round spermatids; Esp, elongated spermatids. (D) Immunofluorescence, using anti-Cyp17, anti-3β-HSD, or anti-Cyp11a antibodies as markers of mature Leydig cells. (E) Testis size and (F) testis weight normalized to BW (mg/g of BW) in Lhb–/– mice injected with PBS (n = 8), osteocalcin (n = 4), or hCG (n = 3) compared with WT mice. All analyses were performed on nonbreeder C57BL/6J mice. Scale bar: 100 μm. *P < 0.05; **P < 0.01.