title: A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys.
abstract: Activin A belongs to the TGF-beta superfamily and plays an important role in bone metabolism. It was reported that a soluble form of extracellular domain of the activin receptor type IIA (ActRIIA) fused to the Fc domain of murine IgG, an activin antagonist, has an anabolic effect on bone in intact and ovariectomized mice. The present study was designed to examine the skeletal effect of human ActRIIA-IgG1-Fc (ACE-011) in non-human primates. Young adult female Cynomolgus monkeys were given a biweekly subcutaneous injection of either 10mg/kg ACE-011 or vehicle (VEH) for 3months. Treatment effects were evaluated by histomorphometric analysis of the distal femur, femoral midshaft, femoral neck and 12th thoracic vertebrae, by muCT analysis of femoral neck and by biomarkers of bone turnover. Compared to VEH, at the distal femur ACE-011-treated monkeys had significantly increased cancellous bone volume (+93%), bone formation rate per bone surface (+166%) and osteoblast surface (+196%) indicating an anabolic action. Monkeys treated with ACE-011 also had decreased osteoclast surface and number. No differences were observed in parameters of cortical bone at the midshaft of the femur. Similar to distal femur, ACE-011-treated monkeys had significantly greater cancellous bone volume, bone formation rate and osteoblast surface at the femoral neck relative to VEH. A significant increase in bone formation rate and osteoblast surface with a decrease in osteoclast surface was observed in thoracic vertebrae. muCT analysis of femoral neck indicated more plate-like structure in ACE-011-treated monkeys. Monkeys treated with ACE-011 had no effect on serum bone-specific alkaline phosphatase and CTX at the end of the study. These observations demonstrate that ACE-011 is a dual anabolic-antiresorptive compound, improving cancellous bone volume by promoting bone formation and inhibiting bone resorption in non-human primates. Thus, soluble ActRIIA fusion protein may be useful in the prevention and/or treatment of osteoporosis and other diseases involving accelerated bone loss.
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA. sutada_lotinun@hsdm.harvard.edu
authors.forename: Sutada
authors.initials: S
authors.lastname: Lotinun
authors.forename: R Scott
authors.initials: RS
authors.lastname: Pearsall
authors.forename: Monique V
authors.initials: MV
authors.lastname: Davies
authors.forename: Tod H
authors.initials: TH
authors.lastname: Marvell
authors.forename: Travis E
authors.initials: TE
authors.lastname: Monnell
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ucran
authors.forename: Roberto J
authors.initials: RJ
authors.lastname: Fajardo
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kumar
authors.forename: Kathryn W
authors.initials: KW
authors.lastname: Underwood
authors.forename: Jasbir
authors.initials: J
authors.lastname: Seehra
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000502:physiology*; D002452:Cell Count; D024042:Collagen Type I / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005269:Femur / Q000187:drug effects / Q000378:metabolism*; D008252:Macaca fascicularis; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000378:metabolism; D018709:Statistics, Nonparametric; D013904:Thoracic Vertebrae / Q000187:drug effects / Q000378:metabolism*
chemical_list: D028341:Activins; D024042:Collagen Type I; D011993:Recombinant Fusion Proteins; C542017:sotatercept; C422405:activin A