title: Osteoclast polarization is not required for degradation of bone matrix in rachitic FGF23 transgenic mice.
abstract: Hypophosphatemic transgenic (tg) mice overexpressing FGF23 in osteoblasts display disorganized growth plates and reduced bone mineral density characteristic of rickets/osteomalacia. These FGF23 tg mice were used as an in vivo model to examine the relation between osteoclast polarization, secretion of proteolytic enzymes and resorptive activity. Tg mice had increased mRNA expression levels of the osteoblast differentiation marker Runx2 and mineralization-promoting proteins alkaline phosphatase and bone sialoprotein in the long bones compared to wild type (wt) mice. In contrast, expression of alpha1(I) collagen, osteocalcin, dentin matrix protein 1 and osteopontin was unchanged, indicating selective activation of osteoblasts promoting mineralization. The number of osteoclasts was unchanged in tg compared to wt mice, as determined by histomorphometry, serum levels of TRAP 5b activity as well as mRNA expression levels of TRAP and cathepsin K. However, tg mice displayed elevated serum concentrations of C-terminal telopeptide of collagen I (CTX) indicative of increased bone matrix degradation. The majority of osteoclasts in FGF23 tg mice lacked ultrastructural morphological signs of proper polarization. However, they secreted both cathepsin K and MMP-9 at levels comparable to osteoclasts with ruffled borders. Mineralization of bone matrix thus appears essential for inducing osteoclast polarization but not for secretion of osteoclast proteases. Finally, release of CTX by freshly isolated osteoclasts was increased on demineralized compared to mineralized bovine bone slices, indicating that the mineral component limits collagen degradation. We conclude that ruffled borders are implicated in acidification and subsequent demineralization of the bone matrix, however not required for matrix degradation. The data collectively provide evidence that osteoclasts, despite absence of ruffled borders, effectively participate in the degradation of hypomineralized bone matrix in rachitic FGF23 tg mice.
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, F46, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Huddinge, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Hollberg
authors.forename: Richard
authors.initials: R
authors.lastname: Marsell
authors.forename: Maria
authors.initials: M
authors.lastname: Norgård
authors.forename: Tobias
authors.initials: T
authors.lastname: Larsson
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Jonsson
authors.forename: Göran
authors.initials: G
authors.lastname: Andersson
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density; D001857:Bone Matrix / Q000166:cytology / Q000502:physiology; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D002417:Cattle; D016764:Cell Polarity; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology; D051381:Rats; D012279:Rickets / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D015415:Biomarkers; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D015675:Osteocalcin; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse; C534133:Ctsk protein, rat; D020780:Matrix Metalloproteinase 9