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

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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 TGFβ, 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.

Section snippets

Introduction: bone as an endocrine organ

It is widely accepted that estrogens play a critical role in the maintenance of bone homeostasis (Manolagas, 2000) and that the cellular basis of bone loss in post-menopausal women results from de-repression of both osteoblast and osteoclast development by estrogen loss after ovarian failure. The pathophysiology of post-menopausal osteoporosis involves the overproduction of osteoclasts, relative to the increase in osteoblastogenesis, a process that, itself, facilitates the support of osteoclast

Inhibins and Activins: sources and effects on the HPG axis

Inhibin A and Inhibin B are heterodimeric proteins in the TGFβ superfamily composed of αβA or αβB subunits, respectively, that were originally isolated from ovarian follicular fluid (Mason et al., 1985). Inhibins were originally identified and defined based on their ability to suppress pituitary follicle stimulating hormone (FSH) secretion (reviewed in (Vale et al., 1994)). The suppression of FSH by the Inhibins is antagonized by the related homodimeric peptides, Activin A and Activin B.

Activins and Inhibins and the skeleton

Inhibins and Activin A also exert opposing effects on several cells of the hematopoietic lineage, including erythroid (Yu et al., 1987), megakaryocyte (Fujimoto et al., 1991, Okafuji et al., 1995), granulocyte–macrophage lineage cells (Broxmeyer et al., 1988, Scher et al., 1990), as well as cells of the monocyte/macrophage lineage (Yamada et al., 1992, Fuller et al., 2000, Gaddy-Kurten et al., 2002, Perrien et al., 2006). Activin βA subunit mRNA is locally produced in bone marrow (Yu et al.,

Activin effects on osteoblastogenesis

Several investigators have explored the effects of Activin A on osteoblast development, using multiple in vitro models. Both primary cells and osteoblastic cell lines of murine, rat and human origin have been used. Results demonstrate opposing effects of Activin on osteoblastogenesis depending upon the model systems and species used. Thus, the evidence will be presented separately for each model.

Activin and osteoclastogenesis

One of the consequences of stimulating osteoblastogenesis is the production of critical pro-osteoclastogenic molecules, such as the receptor activator of NFkB ligand (RANKL) and mCSF, thereby providing the foundation for the coupling of osteoblastogenesis and osteoclastogenesis (Manolagas, 2000, Horowitz et al., 2001, Teitelbaum and Ross, 2003, Martin et al., 2006). Although Activin A has been shown to exert both stimulatory and suppressive effects on in vitro osteoblast development, Activin A

Activin effects in vivo

Similar to the paradoxical in vitro effects of Activin A on osteoblastogenesis, conflicting skeletal effects of Activin A in vivo have also been reported. Stimulatory effects of Activin A treatment on bone mass have been observed in several systems. Local injection over the periosteum of neonatal calvaria increased bone formation (Oue et al., 1994), and direct injection into rat fibula fracture sites enhanced both callus and bone formation (Sakai et al., 1999). In addition, intramuscular

Inhibin effects on osteoblastogenesis and osteoclastogenesis

As has been demonstrated with many Activin target tissues, Inhibins exert dominant and opposing effects to Activin on both osteoblast and osteoclast development (Gaddy-Kurten et al., 2002). Both Inhibin A and Inhibin B isoforms suppressed osteoblast and osteoclast development in murine bone marrow cultures (Gaddy-Kurten et al., 2002), human mesenchymal stem cells (hMSC), and peripheral blood mononuclear cells (PBMC), respectively (Perrien et al., 2006). Inhibin treatment blocked recruitment of

Correlation of Inhibins with bone turnover in humans

The demonstration that Inhibins exert direct effects on osteoblastogenesis and osteoclastogenesis suggested that Inhibins may have a clinically relevant role in bone turnover. Decreases in serum Inhibin B are the first indicators of loss of ovarian function at the onset of menopause, causing de-repression of pituitary FSH secretion (Klein et al., 1996, Klein et al., 2004, Welt et al., 1999). Moreover, serum FSH was demonstrated to be a better predictor than estradiol of the earliest

Inhibin effects in vivo

The effects of Inhibins on the regulation of bone mass have been less well studied. This is in part due to the limited quantities and costs of commercially available recombinant Inhibins. However, transgenic mouse models have been used to inducibly express recombinant human Inhibin A at in intact and gonadectomized mice (Perrien et al., 2007). Continuous systemic exposure to Inhibin A for 4 weeks was strongly anabolic in intact adult mice at multiple skeletal sites, including the tibia, spine

Conclusions

Collectively, significant evidence has accumulated demonstrating in vitro and in vivo effects of both Activins and Inhibins on osteoblast and osteoclast development (summarized in Table 2). The data provide overwhelming evidence to suggest that reproductive hormones other than sex steroids play an important role in regulating both bone mass and bone strength. However, the specific roles that Inhibins and Activins play in regulating bone metabolism remains far from clear. Activins have

Acknowledgements

Our studies of the action of activin and inhibin in bone have been supported by NIH grants R01-DK54044 and R21-DK74024 (DG) and F31-DK079362 (KMN), The Porter Physiology Developmental Fellowship (KMN), the NASA Graduate Student Research Program (DSP), and the Carl L. Nelson Chair of Orthopaedic Creativity (LJS).

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