The effects of reproductive hormones on bone: The role of inhibin A

Abstract

Inhibins (Inh) A and B are gonadal peptide members of the transforming growth factor-β superfamily that are negative feedback regulators of pituitary follicle stimulating hormone (FSH). We and others have shown that decreases in Inh correlate with increases in bone formation and resorption across the menopause transition, and that Inh levels predict lumbar bone mass in perimenopausal women. These changes are due to direct Inh suppression of differentiation of bone forming cells (osteoblasts, OB) and bone resorbing cells (osteoclasts, OCL). InhA suppressed in vitro OCL formation and bone resorption, even in the presence of FSH, demonstrating the dominant suppressive effect of InhA. In clinical studies, InhA was shown to be the best endocrine predictor of bone biochemical markers in pre and perimenopausal women, independent of changes in FSH or estradiol. In addition to being an endocrine regulator of bone turnover, continuous InhA exposure in vivo is anabolic. In an inducible InhA transgenic model and in adult mice exposed to continuous physiological levels of InhA, trabecular bone volume and architecture in the tibia, humerus and spine were significantly increased. InhA increased cortical bone geometry parameters, including cortical cross sectional area and thickness, suggesting increases in bone strength. The cellular target of InhA anabolism was primarily cells of the osteoblastic lineage, since increased OB activity via osteoid thickness, mineral apposition and bone formation rates was observed. In vivo InhA exposure increased bone marrow mesenchymal cell recruitment into the osteoblastic lineage in ex vivo cultures. In contrast, bone resorption and OCL parameters in vivo were not significantly altered. The molecular mechanisms involved in Inh action on bone have yet to be determined. However, our microarray analysis revealed the candidate genes, IGF-1 and VEGFA, as potential mediators of Inh action in bone. It was determined that InhA effects on osteoclastogenesis occurred independently of Wnt signaling. Collectively, these data support our hypothesis that Inhibins are important components of the endocrine repertoire that regulates bone metabolism involving complex mechanisms of action. Like other endocrine hormones, this action is bimodal, whereby cyclic or short-term Inhibin exposure suppresses bone turnover, and continuous long-term Inhibin exposure is anabolic.