ReviewRegulation of osteoblastogenesis and osteoclastogenesis by the other reproductive hormones, Activin and Inhibin
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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2021, BoneCitation Excerpt :The only genes to increase their magnitude by at least 1.0 FC from day 1 to day 5 were Inhba (2.5 to 3.5) and Wnt1 (1.5 to 5.1). Inhba can form subunits for activin or inhibin which both have important roles in modulating TGF-ꞵ and BMP signaling, and have been shown to affect differentiation of osteoblasts and osteoclasts [52]. Wnt1 has been noted previously as a loading-induced gene in bone [14–16,20].
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2021, Cytokine and Growth Factor ReviewsCitation Excerpt :Although a definitive role for activin A in MM has not been firmly established, several groups have reported that elevated activin A blood plasma levels associate with advanced-stage disease, as indicated both by the degrees of plasma cell infiltration of the bone marrow and the levels of osteolysis in patients [106,107]. Mechanistically it is suggested that activin A enhances osteolytic bone destruction in MM patients by magnifying its natural biological role in bone remodeling, which includes activating bone-resorbing osteoclasts and inhibiting differentiation of bone-forming osteoblasts [108]. Supporting this view, ActRIIA-Fc increased bone formation and osteoblast number and reduced osteolytic lesions and the number of tumor cells in two distinct MM mouse models, providing direct evidence that activin antagonism has significant therapeutic potential for treating MM [106,109].
Infraphysiological 17β-estradiol (E2) concentration compromises osteoblast differentiation through Src stimulation of cell proliferation and ECM remodeling stimulus
2020, Molecular and Cellular EndocrinologyCitation Excerpt :It is well known that the estrogen hormone, 17β-estradiol (E2) acts on osteoblasts through nuclear receptors and regulates the cytokines involved in bone remodeling (Kisakol et al., 2003). The activation of osteoclastogenesis via the receptor activator of the nuclear factor kappa-Β (RANK)/receptor of the nuclear factor kappa-Β ligand (RANKL) is well known (Menezes et al., 2006), but the role that the genes involved in osteoblastic differentiation play in responding to E2 remains little known (Nicks et al., 2009). E2 deficiency in the body establishes an imbalance in the activity of bone cells, mainly in relation to the coupling of osteoclasts and osteoblasts, and this culminates in a disruption of the synchrony required for bone remodeling, resulting in increased bone loss and subsequent osteoporosis, mainly occurring in postmenopausal women (Nicks et al., 2009; Weitzmann and Pacifici, 2006).
Dehydrodiconiferyl alcohol promotes BMP-2-induced osteoblastogenesis through its agonistic effects on estrogen receptor
2018, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Bone formation is mediated by osteoblasts, which is a terminally differentiated form of mesenchymal stem cells [6]. Osteoblastogenesis, namely the differentiation process of osteoblasts from precursor cells, is regulated by endocrine and paracrine factors such as estrogen and growth factors that activate a variety of intracellular signaling pathways [7]. In osteoblastogenesis, BMP-2 (bone morphogenetic protein-2) plays a master role in the regulation of various genes involved in osteoblast functions such as RUNX2 (runt-related transcriptional factor 2), ALP (alkaline phosphatase), osteocalcin and OPG (osteoprotegerin), by activating the Smad signaling pathway [8–11].
Mechanisms of BMP-Receptor Interaction and Activation
2015, Vitamins and HormonesCitation Excerpt :Their pleiotropic nature is further visible from their involvement in the organogenesis of various organs (e.g., kidney, pancreas, the heart, or the eye) (for review: Asashima, Ariizumi, & Malacinski, 2000) or their functions in inflammation and immunity (for review: Phillips, de Kretser, & Hedger, 2009). And even though Activins are no direct osteogenic factors as different BMPs, they—by various mechanisms—regulate the differentiation and proliferation of bone cells, skeletal development, and bone turnover with the two isoforms ActivinβA and ActivinβB seemingly exerting differing functions (for review: Lotinun, Pearsall, Horne, & Baron, 2012; Nicks, Perrien, Akel, Suva, & Gaddy, 2009). Due to their role in bone homeostasis, Activin traps such as soluble Activin receptor-Fc fusion proteins have become interesting alternatives for future therapies of bone-loss diseases such as osteoporosis (Fajardo et al., 2010; Lotinun et al., 2010; Pearsall et al., 2008).