Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis
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
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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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 3

The osteocalcin reproductive function is hampered in the absence of proper bone resorption.

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The osteocalcin reproductive function is hampered in the absence of prop...
(A) Schematic representation of the strategy used to generate Ctsk-Cre;DTAfl/+ male mice. (B–D) Histological and histomorphometric analyses of vertebrae in control (n = 8) and Ctsk-Cre;DTAfl/+ (n = 9) male mice 4 months after transplantation. (B) Von Kossa/Van Giesen staining. Bone volume over trabecular volume (BV/TV%) is indicated below the pictures. (C) TRAP staining to reveal osteoclasts. Osteoclast surface per bone surface (Oc.S/BS [%]) and number of osteoclasts per bone trabecular surface (N. Oc/Bpm [1 mm]) are indicated below the pictures. (D) Toluidine blue staining showing an important presence of cartilage remnants (indicated by the asterisk) in Ctsk-Cre;DTAfl/+ male mice versus WT. (E) Measurement of uncarboxylated, carboxylated, total, and undercarboxylated forms of osteocalcin in the serum of 10-week-old Ctsk-Cre;DTAfl/+ versus WT male mice. (F) Sperm counts and (G) circulating testosterone levels; (H–J) testis, epididymal, and seminal vesicle weights normalized to BW (mg/g of BW) in Ctsk-Cre;DTAfl/+ (n = 12) versus WT (n = 11) male mice. (K) Circulating LH measurement in control and Ctsk-Cre;DTAfl/+ mice. (L) qPCR analysis of the expression of steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (Cyp11a), cytochrome P-450 17 α (Cyp17), 3-β-hydroxysteroid dehydrogenase (3β-HSD), aromatase enzyme (Cyp19), and 17- β-hydroxysteroid dehydrogenase (HSD-17) in Ctsk-Cre;DTAfl/+ (n = 12) compared with WT (n = 11) male mice. All analyses presented were performed on nonbreeder C57BL/6J mice. Scale bars: 200 μm). *P < 0.05; **P < 0.01; ***P < 0.001.