title: 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.
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA. Electronic address: peter.bialek@pfizer.com.
authors: P
authors: P
authors: Bialek
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: J
authors: J
authors: Parkington
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: X
authors: X
authors: Li
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: D
authors: D
authors: Gavin
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: C
authors: C
authors: Wallace
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: J
authors: J
authors: Zhang
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: A
authors: A
authors: Root
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: G
authors: G
authors: Yan
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: L
authors: L
authors: Warner
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: H J
authors: HJ
authors: Seeherman
authors: Biotherapeutics Research and Development, Pfizer Inc., 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: P J
authors: PJ
authors: Yaworsky
mesh_terms: D029404:Activin Receptors / Q000378:metabolism*; D045930:Anabolic Agents / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D055398:Bone Morphogenetic Protein 3 / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000033:anatomy & histology / Q000187:drug effects; D055435:Myostatin / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D010281:Parathyroid Hormone / Q000494:pharmacology; D011961:Receptors, Fc / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D045930:Anabolic Agents; D000911:Antibodies, Monoclonal; D055398:Bone Morphogenetic Protein 3; C525912:Mstn protein, mouse; D055435:Myostatin; D010281:Parathyroid Hormone; D011961:Receptors, Fc; D029404:Activin Receptors
keywords: ActRIIB-Fc; BMP3; Bone histomorphometry; Mechanical testing; Myostatin; Rodent