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

Nicks, Kristy M.; Perrien, Daniel S.; Akel, Nisreen; Suva, Larry J.; Gaddy, Dana

doi:10.1016/j.mce.2009.07.001

Cited by 48 publications

(48 citation statements)

References 112 publications

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“…In vivo, TGFb does not prevent bone loss induced by ovariectomy (76) but prevents immobilization-related bone loss caused by decreased osteoblastogenesis (77,78). Inhibins (Inh), activins, and myostatins (GDF8) are other members of the TGFb superfamily that control bone metabolism (79). InhA overexpression was found to prevent gonadectomyinduced bone loss (80).…”

Section: Growth Factorsmentioning

confidence: 99%

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Marie¹,

Kassem²

2011

European Journal of Endocrinology

188

143

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Objective: Age-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass and increase in bone fragility has been based on inhibition of bone resorption using anticatabolic drugs. The current challenge is to promote osteoblastogenesis and bone formation to prevent age-related bone deterioration. Methods: A limited number of approved therapeutic molecules are available to activate bone formation. Therefore, there is a need for anabolic drugs that promote bone matrix apposition at the endosteal, endocortical, and periosteal envelopes by increasing the number of osteoblast precursor cells and/or the function of mature osteoblasts. In this study, we review current therapeutics promoting bone formation and anabolic molecules targeting signaling pathways involved in osteoblastogenesis, based on selected full-text articles searched on Medline search from 1990 to 2010. Results and discussion: We present current therapeutic approaches focused on intermittent parathyroid hormone and Wnt signaling agonists/antagonists. We also discuss novel approaches for prevention and treatment of defective bone formation and bone loss associated with aging and osteoporosis. These strategies targeting osteoblastic cell functions may prove to be useful in promoting bone formation and improving bone strength in the aging population.

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Section: Growth Factorsmentioning

confidence: 99%

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Marie¹,

Kassem²

2011

European Journal of Endocrinology

188

143

View full text Add to dashboard Cite

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“…BMPs therefore can utilize ACVR2A/B and also the BMP-specific type 2 receptor, BMPR2, allowing for potential competition for ACVR2A/B by BMPs and activin based on the availability of BMPR2. We examined this hypothesis in the context of the mouse skeleton, taking advantage of the fact that postnatal bone formation and mineralization is under tight reciprocal regulation by BMPs and activins (Alves et al, 2013;Eijken et al, 2007;Fajardo et al, 2010;Ikenoue et al, 1999;Koncarevic et al, 2010;Li et al, 2013;Lotinun et al, 2010;Matsumoto et al, 2012;Mishina et al, 2004;Nicks et al, 2009;Pearsall et al, 2008;Perrien et al, 2007;Ruckle et al, 2009;Sakai et al, 2000;Sherman et al, 2013;Simic et al, 2006;Zhang et al, 2009;Zhao et al, 2002). Surprisingly, engineering specific deletion of BMPR2 in bone-forming cells (Bmpr2-cKO mice) selectively reduces activin pathway activation but has no apparent effect on BMP signaling.…”

Section: Introductionmentioning

confidence: 99%

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

Lowery

Intini

Gamer

et al. 2015

Journal of Cell Science

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Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFb signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFb signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level competition between BMPs and activins and where utilization of ACVR2A and ACVR2B by BMPs comes at the expense of activins. As BMP and activin pathway modulation are of current therapeutic interest, our findings provide important mechanistic insight into the relationship between these pathways in human health.

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“…In addition to storage in the bone matrix, ActA is an endogenous growth factor produced during ex vivo bone marrow cell osteoblast development, where it has the ability to enhance the formation of both bone forming osteoblasts and bone resorbing OCLs (Fuller et al, 2000;Gaddy-Kurten et al, 2002;Nicks et al, 2009;Silbermann et al, 2014). This appears to be the case in humans, and several investigators have suggested an important role for ActA in the fundamental process of bone remodeling (Pearsall et al, 2008;Teitelbaum and Ross, 2003), which is responsible for the maintenance of skeletal integrity (Suva et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

Fowler

Kamalakar

Akel

et al. 2015

Journal of Cell Science

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BSTRACTThe process of osteoclastic bone resorption is complex and regulated at multiple levels. The role of osteoclast (OCL) fusion and motility in bone resorption are unclear, with the movement of OCL on bone largely unexplored. RANKL (also known as TNFSF11) is a potent stimulator of murine osteoclastogenesis, and activin A (ActA) enhances that stimulation in whole bone marrow. ActA treatment does not induce osteoclastogenesis in stroma-free murine bone marrow macrophage cultures (BMM), but rather inhibits RANKL-induced osteoclastogenesis. We hypothesized that ActA and RANKL differentially regulate osteoclastogenesis by modulating OCL precursors and mature OCL migration. Time-lapse video microscopy measured ActA and RANKL effects on BMM and OCL motility and function. ActA completely inhibited RANKLstimulated OCL motility, differentiation and bone resorption, through a mechanism mediated by ActA-dependent changes in SMAD2, AKT1 and inhibitor of nuclear factor kB (IkB) signaling. The potent and dominant inhibitory effect of ActA was associated with decreased OCL lifespan because ActA significantly increased activated caspase-3 in mature OCL and OCL precursors.Collectively, these data demonstrate a dual action for ActA on murine OCLs.

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

Cited by 48 publications

References 112 publications

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

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