Introduction: Current therapeutics for osteogenesis imperfecta (OI), a heritable connective tissue disorder characterized by skeletal fragility and impaired bone cell function, are limited to bisphosphonates. Soluble activin receptor type IIB (sActRIIB) decoy molecules, which bind transforming growth factor-β (TGF-β) ligands, including myostatin and activin A, have increased skeletal bone properties in murine models of OI, including the mild/moderate G610C mouse model of OI. However, the promiscuity of sActRIIB for multiple ligand targets resulted in adverse effects observed in clinical trials of boys with Duchenne muscular dystrophy and postmenopausal women with osteoporosis. We examined the musculoskeletal effects of inhibiting activin A alone, myostatin alone, or both in wildtype (Wt) and heterozygous G610C (+/G610C) mice using highly specific monoclonal antibodies to determine their role on postnatal musculoskeletal properties.
Methods: Male and female Wt and +/G610C mice were injected intraperitoneally twice weekly with monoclonal control antibody (Ctrl-Ab), anti-activin A antibody (ActA-Ab), anti-myostatin antibody (Mstn-Ab) or both ActA-Ab and Mstn-Ab (Combo,) from 5 to 16 weeks of age. Following euthanasia at 16 weeks of age, femoral microarchitecture and biomechanical strength was evaluated by microCT (µCT) and 3-point bend analyses.
Results: ActA-Ab had minimal effects on femoral microarchitecture in +/G610C mice, actually decreasing bone strength in male +/G610C mice, although Wt male mice exhibited increases in trabecular microarchitecture with ActA-Ab treatment. Mstn-Ab, as previously reported, had minimal skeletal impact in +/G610C mice. Conversely, the Combo treatment out-performed inhibition by ActA-Ab alone or Mstn-Ab alone, consistently improving femoral trabecular and cortical microarchitecture and strength in both male and female +/G610C and Wt mice.
Impact: Combinatorial inhibition of activin A and myostatin more potently increased femoral bone microarchitecture and strength relative to myostatin or activin A inhibition alone, and recaptured the skeletal improvements generated by sActRIIB treatment in +/G610C mice.
Organization – University of Missouri – Columbia
AOmosule CL, Joseph D, Weiler B, Gremminger VL, Jeong Y, Kleiner S, Phillips CL