title: Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues.
abstract: During vertebrate skeletal development, osteoblasts produce a mineralized bone matrix by deposition of hydroxyapatite crystals in the extracellular matrix. Anoctamin6/Tmem16F (Ano6) belongs to a conserved family of transmembrane proteins with chloride channel properties. In addition, Ano6 has been linked to phosphatidylserine (PS) scrambling in the plasma membrane. During skeletogenesis, Ano6 mRNA is expressed in differentiating and mature osteoblasts. Deletion of Ano6 in mice results in reduced skeleton size and skeletal deformities. Molecular analysis revealed that chondrocyte and osteoblast differentiation are not disturbed. However, mutant mice display increased regions of nonmineralized, Ibsp-expressing osteoblasts in the periosteum during embryonic development and increased areas of uncalcified osteoid postnatally. In primary Ano6(-/-) osteoblasts, mineralization is delayed, indicating a cell autonomous function of Ano6. Furthermore, we demonstrate that calcium-dependent PS scrambling is impaired in osteoblasts. Our study is the first to our knowledge to reveal the requirement of Ano6 in PS scrambling in osteoblasts, supporting a function of PS exposure in the deposition of hydroxyapatite.
authors.affiliation: Department of Developmental Biology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
authors.forename: Harald W A
authors.initials: HW
authors.lastname: Ehlen
authors.forename: Milana
authors.initials: M
authors.lastname: Chinenkova
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Hans-Markus
authors.initials: HM
authors.lastname: Munter
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Krause
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gross
authors.forename: Bent
authors.initials: B
authors.lastname: Brachvogel
authors.forename: Manuela
authors.initials: M
authors.lastname: Wuelling
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.forename: Andrea
authors.initials: A
authors.lastname: Vortkamp
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000075368:Anoctamins; D001692:Biological Transport; D001842:Bone and Bones / Q000378:metabolism*; D002113:Calcification, Physiologic; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010718:Phosphatidylserines / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins / Q000172:deficiency / Q000378:metabolism*; D012886:Skull / Q000473:pathology
chemical_list: C576687:ANO6 protein, mouse; D000075368:Anoctamins; D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins