A Soluble Activin Receptor Type IIB Prevents the Effects of Androgen Deprivation on Body Composition and Bone Health

Abstract

Androgen deprivation, a consequence of hypogonadism, certain cancer treatments, or normal aging in men, leads to loss of muscle mass, increased adiposity, and osteoporosis. In the present study, using a soluble chimeric form of activin receptor type IIB (ActRIIB) we sought to offset the adverse effects of androgen deprivation on muscle, adipose tissue, and bone. Castrated (ORX) or sham-operated (SHAM) mice received either TBS [vehicle-treated (VEH)] or systemic administration of ActRIIB-mFc, a soluble fusion protein comprised of a form of the extracellular domain of ActRIIB fused to a murine IgG2aFc subunit. In vivo body composition imaging demonstrated that ActRIIB-mFc treatment results in increased lean tissue mass of 23% in SHAM mice [19.02 +/- 0.42 g (VEH) versus 23.43 +/- 0.35 g (ActRIIB-mFc), P < 0.00001] and 26% in ORX mice [15.59 +/- 0.26 g (VEH) versus 19.78 +/- 0.26 g (ActRIIB-mFc), P < 0.00001]. Treatment also caused a decrease in adiposity of 30% in SHAM mice [5.03 +/- 0.48 g (VEH) versus 3.53 +/- 0.19 g (ActRIIB-mFc), NS] and 36% in ORX mice [7.12 +/- 0.53 g (VEH) versus 4.57 +/- 0.28 g (ActRIIB-mFc), P < 0.001]. These changes were also accompanied by altered serum levels of leptin, adiponectin, and insulin, as well as by prevention of steatosis (fatty liver) in ActRIIB-mFc-treated ORX mice. Finally, ActRIIB-mFc prevented loss of bone mass in ORX mice as assessed by whole body dual x-ray absorptiometry and micro-computed tomography of proximal tibias. The data demonstrate that treatment with ActRIIB-mFc restored muscle mass, adiposity, and bone quality to normal levels in a mouse model of androgen deprivation, thereby alleviating multiple adverse consequences of such therapy.

Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of duchenne muscular dystrophy

“…The separation of trabeculae was also decreased. Our findings are consistent with previous reports demonstrating that treatment with either ActRIIA-Fc [6,8] or ActRIIBFc [9,10] resulted in increased bone volume. Increased BMD in trabecular bone also suggests that at least part of the effect could be derived from decreased bone resorption, possibly due to slower bone turnover and prolonged secondary mineralization and filling of resorption N) and (e) volumetric bone mineral density (vBMD) were increased while (f) trabecular separation (Tb.…”

“…The use of a soluble activin type IIA-receptor has been shown to increase bone mass in several in vivo [5,6,8] models. The effects of soluble activin type IIB-receptor (ActRIIB-Fc) on bone metabolism have also been studied recently [9][10][11][12]. Furthermore, exercise, in addition to its various other health benefits, may have positive effects on bones of young individuals [13,14].…”

Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis

“…146 A similar soluble chimeric form of activin receptor type IIB (ActRIIB) fused to a murine IgG2aFc subunit was also tested and prevented loss of bone mass in gonadectomized male mice as assessed by whole body DXA and micro-computed tomography of proximal tibias. 143 Another fusion protein of the extracellular domain of the ActRIIA linked to human IgG1-Fc (sotatercept -ACE-011) has also been developed. Within only 3 months, biweekly subcutaneous ACE-011 at a dose of 10mg/kg in primates increased bone mass by 13-15% and trabecular bone volume over 70%.…”

“…By contrast, several studies demonstrated an inhibitory effect of activin A on osteoblast differentiation in murine, rat, and human cell cultures in vitro. [138][139][140] On the other hand, activin A seems to exert a stimulatory effect in osteoclastogenesis and increases bone resorption via ActRIIA signaling; [141][142][143] this could also result indirectly through stimulation of FSH release, which appears to promote osteoclastogenesis as well. 144,145 In contrast, inhibins inhibit osteoclastogenic differentiation in bone marrow cultures, 141 while they increase osteoblast differentiation in mice bearing the human inhibin A gene.…”

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

“…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.…”