title: Progressive ankylosis protein (ANK) in osteoblasts and osteoclasts controls bone formation and bone remodeling.
abstract: The progressive ankylosis gene (ank) encodes a transmembrane protein that transports intracellular inorganic pyrophosphate (PP(i)) to the extracellular milieu. ank/ank mice, which express a truncated nonfunctional ANK, showed a markedly reduced bone mass, bone-formation rate, and number of tartrate-resistant acid phosphatase-positive (TRAP(+)) multinucleated osteoclasts. ANK function deficiency suppressed osteoblastic differentiation of ank/ank bone marrow stromal cells, as indicated by the decrease in the expression of bone marker genes, including osterix, reduced alkaline phosphatase activity, and mineralization. Runx2 gene expression levels were not altered. Conversely, overexpression of ANK in the preosteoblastic cell line MC3T3-E1 resulted in increased expression of bone marker genes, including osterix. Whereas runx2 expression was not altered in ANK-overexpressing MC3T3-E1 cells, runx2 transcriptional activity was increased. Extracellular PP(i) or P(i) stimulated osteoblastogenic differentiation of MC3T3-E1 cells or partially rescued delayed osteoblastogenic differentiation of ank/ank bone marrow stromal cells. A loss of PP(i) transport function ANK mutation also stimulated osteoblastogenic differentiation of MC3T3-E1 cells. Furthermore, ANK function deficiency suppressed the formation of multinucleated osteoclasts from ank/ank bone marrow cells cultured in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor-kappaB ligand. In conclusion, ANK is a positive regulator of osteoblastic and osteoclastic differentiation events toward a mature osteoblastic and osteoclastic phenotype.
authors.affiliation: Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University Hospital for Joint Diseases, New York, NY, USA.
authors.forename: Hyon Jong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Takeshi
authors.initials: T
authors.lastname: Minashima
authors.forename: Edward F
authors.initials: EF
authors.lastname: McCarthy
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kirsch
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016723:Bone Remodeling / Q000502:physiology*; D002113:Calcification, Physiologic / Q000502:physiology; D002452:Cell Count; D002454:Cell Differentiation; D002469:Cell Separation; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005269:Femur / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000502:physiology*; D028061:Phosphate Transport Proteins; D012886:Skull / Q000473:pathology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D013977:Tibia / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D008565:Membrane Proteins; D050505:Mutant Proteins; D028061:Phosphate Transport Proteins; C493716:Runx2 protein, mouse; C410982:ank protein, mouse