Hypoxia signaling pathway activation in osteoblasts suppresses osteocalcin production but does not alter male fertility in mice

Introduction/objective Bone can contribute to systemic and extra-skeletal processes through bone-derived hormones. The osteoblast-specific protein osteocalcin (OCN) has been reported to positively regulate male fertility, by directly favouring testicular testosterone biosynthesis. We previously demonstrated that aberrant hypoxia-inducible factor (HIF) signaling in osteoprogenitors drastically changes bone properties associated with suppressed OCN expression. This led us to question whether hypoxia signaling in bone could be an upstream determinant of male fertility, by indirectly impacting testosterone production and testicular function through bone-derived OCN. Design/methods To investigate the impact of hypoxia pathway activation in osteoprogenitors and/or osteoblasts on male fertility, we genetically deleted the negative HIF-regulator von Hippel-Lindau (VHL) in mice using two independent osteolineage-targeted Cre lines. In these Vhl conditional knockout (cKO) strains, we investigated OCN production, testosterone biosynthesis, testicular morphology and male fertility, including functional evaluation of reproductive capacity. Results Our data demonstrate that loss of VHL in osteolineage cells consistently and strongly reduces the production of OCN in bone, leading to very low circulating levels of both carboxylated and undercarboxylated OCN. Testicular expression of selected enzymes of the testosterone biosynthesis pathway was decreased in Vhl cKO mice. However, our data did not show significant deficiencies in testosterone levels, reproductive organs’ weights, Leydig cell mass, sperm count, or breeding efficiency in the two strains of skeletal Vhl cKO mice. Conclusions These findings indicate that aberrant hypoxia signaling in bone suppresses OCN production without compromising male fertility, possibly reflecting a role for the broader physiological context as critical modulator of OCN’s endocrine activity.