This study demonstrated that ActRIIB-Fc increased trabecular bone volume in Bmp3−/− mice and their WT littermates to the same extent. If BMP3 inhibition by ActRIIB-Fc was primarily responsible for the increased bone mass, then BV/TV should be similar to WT mice

treated with ActRIIB-Fc compared to Bmp3−/− controls and that ActRIIB-Fc would not increase BV/TV in the Bmp3−/− animals. The observation that ActRIIB-Fc significantly increased bone mass in Bmp3 null mice to the same extent as WT mice suggests that BMP3 neutralization is not required for the anabolic activity of ActRIIB-Fc on bone. Increased bone mineral density following treatment with ActRIIA-Fc in Bmp3−/− mice was previously reported but this is first report to demonstrate this by ActRIIB-Fc [31], [51] and [52]. ActivinA is also Erastin purchase highly expressed in bone but the role of activins and their antagonists in bone metabolism both in vitro and in vivo has demonstrated conflicting results [53]. In bone-marrow

derived osteoclast cultures, activinA stimulates osteoclastogenesis while its effects on cultured osteoblasts is less clear [54] and [55]. In vivo, activinA has been shown to promote callus formation when directly Osimertinib molecular weight applied to the fracture site [56]. Furthermore, activinA administration can increase bone mineral density in vertebrae of aged ovariectomized rats [57]. In contrast, transgenic over expression of inhibin, an antagonist of activinA activity, increased bone formation, bone mass and strength [58]. Administration of a soluble decoy receptor of activinA, ActRIIA-mFc, was reported to increase trabecular bone mass and strength by stimulating osteoblast activity [31]. This phenotype is very similar to ActRIIB-Fc treatment although there are some distinct differences. Both agents not increased bone mass to a similar extent by stimulating osteoblast activity as measured by dynamic histomorphometry. However only ActRIIA-mFc increased serum osteocalcin expression. Prolonged treatment of ActRIIA-mFc also resulted

in increased cortical bone thickness and enhanced femoral strength which was not observed in our shorter ActRIIB-Fc treatment. The similarities in bone phenotypes between ActRIIB-Fc and ActRIIA-Fc certainly suggest that both molecules may antagonize a common ligand or group of ligands responsible for regulating bone mass. ActRIIB-Fc inhibits activinA, activinB and activinAB in cell-based reporter assays with the similar potency as myostatin [28]. Neutralization of one of the activins may be responsible for the enhanced bone phenotype from either or both decoy-receptors. In contrast, ActRIIB-Fc increased muscle mass while ActRIIA-mFc did not, further supporting the hypothesis that some aspects of the regulation of bone mass and muscle mass are independent.