title: Activin receptor signaling: a potential therapeutic target for osteoporosis.
abstract: Current antiresorptive therapies not only prevent bone loss by decreasing osteoclastic bone resorption but also inhibit bone formation. Dual anabolic antiresorptive agents may be required to cure severe osteoporosis by preventing further bone loss and increasing bone mass to normal levels. Recent studies have demonstrated that activin signaling plays a crucial role in the skeleton. Activins, like other TGF-β superfamily members, transduce their signals through type I and II receptor serine/threonine kinases. The binding of activins to activin type IIA (ActRIIA) or type IIB (ActRIIB) receptors induces the recruitment and phosphorylation of an activin type I receptor (ALK4 and/or ALK7), which then phosphorylates the Smad2 and Smad3 intracellular signaling proteins. Activin signaling is down-regulated by inhibins, follistatin and other proteins, which antagonize activin signaling by a variety of mechanisms. A soluble chimeric protein composed of the extracellular domain of ActRIIA fused to IgG-Fc binds to circulating ligands such as activin A and prevents signaling through the endogenous receptor. In cynomolgus monkeys, the ActRIIA soluble receptor increases bone volume by decreasing bone resorption and increasing bone formation, leading to enhanced mechanical strength and bone quality. In addition, a single dose of the soluble ActRIIA-Fc fusion protein increased serum BSALP and PINP and decreased serum CTX and TRACP 5b in postmenopausal women. These data provide evidence of a dual anabolic antiresorptive effect of the soluble ActRIIA-Fc fusion protein in the skeleton. Therefore, targeting activin receptor signaling may be useful for therapeutic intervention in osteoporosis.
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: William C
authors.initials: WC
authors.lastname: Horne
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
mesh_terms: D029404:Activin Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism; D028341:Activins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000378:metabolism; D006801:Humans; D010024:Osteoporosis / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D050071:Bone Density Conservation Agents; D011993:Recombinant Fusion Proteins; D028341:Activins; D029404:Activin Receptors; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II