title: Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures.
abstract: The process of osteoclastic bone resorption is complex and regulated at multiple levels. The role of osteoclast (OCL) fusion and motility in bone resorption are unclear, with the movement of OCL on bone largely unexplored. RANKL (also known as TNFSF11) is a potent stimulator of murine osteoclastogenesis, and activin A (ActA) enhances that stimulation in whole bone marrow. ActA treatment does not induce osteoclastogenesis in stroma-free murine bone marrow macrophage cultures (BMM), but rather inhibits RANKL-induced osteoclastogenesis. We hypothesized that ActA and RANKL differentially regulate osteoclastogenesis by modulating OCL precursors and mature OCL migration. Time-lapse video microscopy measured ActA and RANKL effects on BMM and OCL motility and function. ActA completely inhibited RANKL-stimulated OCL motility, differentiation and bone resorption, through a mechanism mediated by ActA-dependent changes in SMAD2, AKT1 and inhibitor of nuclear factor κB (IκB) signaling. The potent and dominant inhibitory effect of ActA was associated with decreased OCL lifespan because ActA significantly increased activated caspase-3 in mature OCL and OCL precursors. Collectively, these data demonstrate a dual action for ActA on murine OCLs.
authors.affiliation: Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA gaddydana@uams.edu.
authors.forename: Tristan W
authors.initials: TW
authors.lastname: Fowler
authors.affiliation: Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Kamalakar
authors.affiliation: Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA.
authors.forename: Nisreen S
authors.initials: NS
authors.lastname: Akel
authors.affiliation: Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Kurten
authors.affiliation: Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Suva
authors.affiliation: Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA gaddydana@uams.edu.
authors.forename: Dana
authors.initials: D
authors.lastname: Gaddy
mesh_terms: D028341:Activins / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001862:Bone Resorption / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D056657:Cathepsin K / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D051550:I-kappa B Kinase / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D051899:Smad2 Protein / Q000378:metabolism
chemical_list: D053245:RANK Ligand; D011994:Recombinant Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C505689:Tnfsf11 protein, mouse; C422405:activin A; D028341:Activins; D016173:Macrophage Colony-Stimulating Factor; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D056657:Cathepsin K; C534132:Ctsk protein, mouse
keywords: Activin A; INHBA; Motility; Osteoclast