title: Mutation in Osteoactivin Promotes Receptor Activator of NFκB Ligand (RANKL)-mediated Osteoclast Differentiation and Survival but Inhibits Osteoclast Function.
abstract: We previously reported on the importance of osteoactivin (OA/Gpnmb) in osteogenesis. In this study, we examined the role of OA in osteoclastogenesis, using mice with a nonsense mutation in the Gpnmb gene (D2J) and wild-type controls (D2J/Gpnmb(+)). In these D2J mice, micro-computed tomography and histomorphometric analyses revealed increased cortical thickness, whereas total porosity and eroded surface were significantly reduced in D2J mice compared with wild-type controls, and these results were corroborated by lower serum levels of CTX-1. Contrary to these observations and counterintuitively, temporal gene expression analyses supported up-regulated osteoclastogenesis in D2J mice and increased osteoclast differentiation rates ex vivo, marked by increased number and size. The finding that MAPK was activated in early differentiating and mature D2J osteoclasts and that survival of D2J osteoclasts was enhanced and mediated by activation of the AKT-GSK3β pathway supports this observation. Furthermore, this was abrogated by the addition of recombinant OA to cultures, which restored osteoclastogenesis to wild-type levels. Moreover, mix and match co-cultures demonstrated an induction of osteoclastogenesis in D2J osteoblasts co-cultured with osteoclasts of D2J or wild-type. Last, in functional osteo-assays, we show that bone resorption activity of D2J osteoclasts is dramatically reduced, and these osteoclasts present an abnormal ruffled border over the bone surface. Collectively, these data support a model whereby OA/Gpnmb acts as a negative regulator of osteoclast differentiation and survival but not function by inhibiting the ERK/AKT signaling pathways.
authors.affiliation: From the Department of Anatomy and Neurobiology, Northeast Ohio Medical University College of Medicine, Rootstown, Ohio 44272.
authors.forename: Samir M
authors.initials: SM
authors.lastname: Abdelmagid
authors.affiliation: From the Department of Anatomy and Neurobiology, Northeast Ohio Medical University College of Medicine, Rootstown, Ohio 44272, the School of Biomedical Sciences and.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Sondag
authors.affiliation: From the Department of Anatomy and Neurobiology, Northeast Ohio Medical University College of Medicine, Rootstown, Ohio 44272, the School of Biomedical Sciences and.
authors.forename: Fouad M
authors.initials: FM
authors.lastname: Moussa
authors.affiliation: the Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, and.
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Belcher
authors.affiliation: From the Department of Anatomy and Neurobiology, Northeast Ohio Medical University College of Medicine, Rootstown, Ohio 44272.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.affiliation: From the Department of Anatomy and Neurobiology, Northeast Ohio Medical University College of Medicine, Rootstown, Ohio 44272.
authors.forename: Hilary
authors.initials: H
authors.lastname: Stinnett
authors.affiliation: From the Department of Anatomy and Neurobiology, Northeast Ohio Medical University College of Medicine, Rootstown, Ohio 44272.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Novak
authors.affiliation: From the Department of Anatomy and Neurobiology, Northeast Ohio Medical University College of Medicine, Rootstown, Ohio 44272.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mbimba
authors.affiliation: From the Department of Anatomy and Neurobiology, Northeast Ohio Medical University College of Medicine, Rootstown, Ohio 44272.
authors.forename: Matthew
authors.initials: M
authors.lastname: Khol
authors.affiliation: the Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Hankenson
authors.affiliation: the School of Biomedical Sciences and Department of Biological Sciences, Kent State University, Kent, Ohio 44240.
authors.forename: Christopher
authors.initials: C
authors.lastname: Malcuit
authors.affiliation: From the Department of Anatomy and Neurobiology, Northeast Ohio Medical University College of Medicine, Rootstown, Ohio 44272, the School of Biomedical Sciences and fayez.safadi@neomed.edu.
authors.forename: Fayez F
authors.initials: FF
authors.lastname: Safadi
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D002454:Cell Differentiation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D005136:Eye Proteins / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008811:Mice, Inbred DBA; D009154:Mutation; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D055114:X-Ray Microtomography
chemical_list: D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D008562:Membrane Glycoproteins; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse
keywords: Akt; MAP kinases (MAPKs); bone; bone marrow; osteoactivin; osteoclast; osteopetrosis
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