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A myostatin and activin decoy receptor enhances bone formation in mice

Bialek, P and Parkington, J and Li, X and Gavin, D and Wallace, C and Zhang, J and Root, A and Yan, G and Warner, L and Seeherman, HJ and Yaworsky, PJ (2014) A myostatin and activin decoy receptor enhances bone formation in mice. Bone. pp. 162-171.

Abstract

Myostatin is a member of the bone morphogenetic protein/transforming growth factor-beta (BMP/TGFbeta) 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. 2013 The Authors

Item Type: Article
Additional Information: NIBR author: Parkington, J institute: NIBR- address only contributor address: (Bialek, Parkington, Li, Gavin, Wallace, Zhang, Root, Yan, Warner, Seeherman, Yaworsky) Biotherapeutics Research and Development, Pfizer Inc., 200 Cambridge Park Drive, Cambridge, MA 02140, United States (Parkington, Zhang) Novartis Institutes for BioMedical Research, Cambridge, MA, United States (Li) Perkin Elmer, Waltham, MA, United States (Warner) Sarepta Therapeutics, Boston, MA, United States (Seeherman) Bioventus, Boston, MA, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22646

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