Regulation of osteoblastogenesis and osteoclastogenesis by the other reproductive hormones, Activin and Inhibin

Abstract

There is both cellular and physiological evidence demonstrating that both Activins and Inhibins regulate osteoblastogenesis and osteoclastogenesis, and regulate bone mass in vivo. Although Activins and Inhibins were initially isolated from the gonad, Activins are also produced and stored in bone, whereas Inhibins exert their regulation on bone cell differentiation and metabolism via endocrine effects. The accumulating data provide evidence that reproductive hormones, distinct from classical sex steroids, are important regulators of bone mass and bone strength. Given the well described dominant antagonism of Inhibin over Activin, as well as over BMPs and TGFbeta, the gonadally derived Inhibins are important regulators of locally produced osteotrophic factors. Thus, the cycling Inhibins in females and diurnal changes in Inhibin B in males elicit temporal shifts in Inhibin levels (tone) that de-repress the pituitary. This fundamental action has the potential to de-repress locally stimulated changes in osteoblastogenesis and osteoclastogenesis, thereby altering bone metabolism.

Figure 1. Skeletal effects of Inhibins, Activin, BMPs and Follistatin derived from bone and gonadal sources

Skeletal effects of Activin A, its antagonist, Follistatin, and BMPs are paracrine effects (…….) from local production and sequestration of peptides in bone matrix. The stimulatory effects of Activin and BMP are blocked by the endocrine effects of Inhibins (- - - -) produced primarily by the gonads. The Inhibin antagonism of Activin and BMP action, demonstrating the importance of skeletal Inhibin “tone” that is associated with normal gonadal function. Activin A and Follistatin are also produced by the gonads, although their levels in serum are likely insufficient to exert endocrine effects on pituitary FSH production or contribute to the regulation of bone metabolism. See text for more details.