title: Adamts1 is highly induced in rachitic bones of FGF23 transgenic mice and participates in degradation of non-mineralized bone matrix collagen.
abstract: Transgenic mice overexpressing fibroblast growth factor 23 (FGF23) in osteoblasts have a rachitic bone phenotype. These mice display hypomineralized bones, increased expression of osteoblast markers, but osteoclast numbers are unaltered or slightly reduced. Paradoxically, they show increased serum levels of the bone resorption marker CTX, a type I collagen degradation fragment. Here we analyzed a matrix metalloproteinase- (MMP-) like secreted protease, Adamts1, that has previously been associated with osteoblastic type I collagen breakdown in vitro. Bones from FGF23 transgenic (tg) mice displayed increased Adamts1 protein upon both immunohistological staining and Western blotting. We further found Adamts1 protein together with excessively degraded type I collagen in the non-mineralized bone fraction of FGF23 tg mice. A similar degradation pattern of type I collagen was noticed upon forced expression of Adamts1 in osteoblastic cells in vitro. Importantly, these Adamts1-expressing osteoblastic cells exhibited increased release of CTX fragments when cultured on demineralized bone discs. Together, these results demonstrate for the first time that Adamts1 can be highly induced in bone tissue and that this MMP-like protease can increase osteoblastic release of CTX fragments from non-mineralized bone. Thus, Adamts1 potentially contributes to the increased serum levels of CTX in rickets/osteomalacia.
authors.affiliation: Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden. lijuan.hu@ki.se
authors.forename: Lijuan
authors.initials: L
authors.lastname: Hu
authors.forename: Göran
authors.initials: G
authors.lastname: Andersson
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Jonsson
authors.forename: Håkan
authors.initials: H
authors.lastname: Melhus
authors.forename: Thomas
authors.initials: T
authors.lastname: Lind
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000071097:ADAMTS1 Protein; D000818:Animals; D015519:Bone Density; D001857:Bone Matrix / Q000378:metabolism*; D002113:Calcification, Physiologic; D024042:Collagen Type I / Q000097:blood / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism; D010018:Osteomalacia / Q000097:blood / Q000378:metabolism*; D059748:Proteolysis; D012279:Rickets / Q000097:blood / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C486323:Adamts1 protein, mouse