Novel ActRIIB ligand trap increases muscle mass and improves bone geometry in a mouse model of severe osteogenesis imperfecta

Osteogenesis imperfecta (OI) caused by mutations affecting the extracellular matrix protein collagen type I is characterized by fragile bones and low muscle mass and function. Activin A and myostatin, members of the TGF-β superfamily, play a key role in the control of muscle mass and in muscle-bone communication. Here we investigated activin A/myostatin signaling in a mouse model of severe dominant OI, Col1a1^Jrt/+mouse, and the effect of activin A/myostatin inhibition by a soluble activin receptor IIB receptor, ACE-2494, on bones and muscles in 8-week old mice. Compared to wild type mice, Col1a1^Jrt/+mice had elevated TGF-β signaling in bone and muscle tissue. ACE-2494 treatment of wild type mice resulted in significantly increased muscle mass, bone length, bone mass as well as improved bone mechanical properties. However, treatment of Col1a1^Jrt/+mice with ACE-2494 was associated with significant gain in muscle mass, significantly improved bone length and bone geometry, but no significant treatment effect was found on bone mass or bone mechanical properties. Thus, our data indicate that activin A/myostatin neutralizing antibody ACE-2494 is effective in stimulating muscle mass, bone length and diaphyseal bone growth but does not correct bone mass phenotype in a mouse model ofdominant OI.