A myostatin and activin decoy receptor enhances bone formation in mice

Abstract

Myostatin is a member of the bone morphogenetic protein/transforming growth factor-β (BMP/TGFβ) super-family of secreted differentiation factors. Myostatin is a negative regulator of muscle mass as shown by increased muscle mass in myostatin deficient mice. Interestingly, these mice also exhibit increased bone mass suggesting that myostatin may also play a role in regulating bone mass. To investigate the role of myostatin in bone, young adult mice were administered with either a myostatin neutralizing antibody (Mstn-mAb), a soluble myostatin decoy receptor (ActRIIB-Fc) or vehicle. While both myostatin inhibitors increased muscle mass, only ActRIIB-Fc increased bone mass. Bone volume fraction (BV/TV), as determined by microCT, was increased by 132% and 27% in the distal femur and lumbar vertebrae, respectively. Histological evaluation demonstrated that increased BV/TV in both locations was attributed to increased trabecular thickness, trabecular number and bone formation rate. Increased BV/TV resulted in enhanced vertebral maximum compressive force compared to untreated animals. The fact that ActRIIB-Fc, but not Mstn-mAb, increased bone volume suggested that this soluble decoy receptor may be binding a ligand other than myostatin, that plays a role in regulating bone mass. This was confirmed by the significant increase in BV/TV in myostatin deficient mice treated with ActRIIB-Fc. Of the other known ActRIIB-Fc ligands, BMP3 has been identified as a negative regulator of bone mass. However, BMP3 deficient mice treated with ActRIIB-Fc showed similar increases in BV/TV as wild type (WT) littermates treated with ActRIIB-Fc. This result suggests that BMP3 neutralization is not the mechanism responsible for increased bone mass. The results of this study demonstrate that ActRIIB-Fc increases both muscle and bone mass in mice. Therefore, a therapeutic that has this dual activity represents a potential approach for the treatment of frailty.

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

“…Surprisingly, competition for ACVR2A/B led to a selective reduction in activin pathway signaling in bone with no apparent alteration in BMP signaling. The high bone mass phenotype we observed in Bmpr2-cKO mice is consistent with previous reports detailing the negative effect of activin on bone formation and matrix mineralization (Alves et al, 2013;Bialek et al, 2013;Eijken et al, 2007;Fajardo et al, 2010;Ikenoue et al, 1999;Koncarevic et al, 2010;Lotinun et al, 2010;Pearsall et al, 2008;Perrien et al, 2007;Ruckle et al, 2009;Sherman et al, 2013).…”

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].…”

“…Myostatin and activins are inhibitors of muscle growth and their inhibition could have therapeutic implications in frailty and other diseases with muscle wasting [4,22]. Intriguingly, ActRIIB-Fc can block both activin A as well as myostatin [23], that could potentially be very beneficial in conditions, such as frailty and DMD, which involve both muscle and bone [9].…”

Inhibiting myostatin signaling prevents femoral trabecular bone loss and microarchitecture deterioration in diet-induced obese rats

“…[25][26][27] On the other hand, MSTN blocking or deficiency has been shown to enhance bone formation. 28,29 However, we still have much to learn regarding whether inhibiting MSTN can reduce obesity-induced bone loss, and if so, what possible mechanisms might be responsible. Our findings demonstrated that blocking MSTN by MsAb preserves bone microstructure and that this effect may involve the accompanying changes occurring in the levels of circulating adiponectin and pro-inflammatory cytokines.…”