title: Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation.
abstract: Extracellular regulation of signaling by transforming growth factor (TGF)-β family members is emerging as a key aspect of organ formation and tissue remodeling. In this study, we demonstrate that fibrillin-1 and -2, the structural components of extracellular microfibrils, differentially regulate TGF-β and bone morphogenetic protein (BMP) bioavailability in bone. Fibrillin-2-null (Fbn2(-/-)) mice display a low bone mass phenotype that is associated with reduced bone formation in vivo and impaired osteoblast maturation in vitro. This Fbn2(-/-) phenotype is accounted for by improper activation of latent TGF-β that selectively blunts expression of osterix, the transcriptional regulator of osteoblast maturation, and collagen I, the structural template for bone mineralization. Cultured osteoblasts from Fbn1(-/-) mice exhibit improper latent TGF-β activation as well, but mature faster because of increased availability of otherwise matrix-bound BMPs. Additional in vitro evidence excludes a direct role of microfibrils in supporting mineral deposition. Together, these findings identify the extracellular microfibrils as critical regulators of bone formation through the modulation of endogenous TGF-β and BMP signaling.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10021, USA.
authors.forename: Harikiran
authors.initials: H
authors.lastname: Nistala
authors.forename: Sui
authors.initials: S
authors.lastname: Lee-Arteaga
authors.forename: Silvia
authors.initials: S
authors.lastname: Smaldone
authors.forename: Gabriella
authors.initials: G
authors.lastname: Siciliano
authors.forename: Luca
authors.initials: L
authors.lastname: Carta
authors.forename: Robert N
authors.initials: RN
authors.lastname: Ono
authors.forename: Gerhard
authors.initials: G
authors.lastname: Sengle
authors.forename: Emilio
authors.initials: E
authors.lastname: Arteaga-Solis
authors.forename: Regis
authors.initials: R
authors.lastname: Levasseur
authors.forename: Patricia
authors.initials: P
authors.lastname: Ducy
authors.forename: Lynn Y
authors.initials: LY
authors.lastname: Sakai
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
mesh_terms: D000818:Animals; D001682:Biological Availability; D001857:Bone Matrix / Q000378:metabolism / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D006801:Humans; D051379:Mice; D020894:Microfibrils / Q000378:metabolism; D008840:Microfilament Proteins / Q000172:deficiency / Q000378:metabolism*; D008954:Models, Biological; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000502:physiology*; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054392:Adipokines
chemical_list: D019485:Bone Morphogenetic Proteins; D003094:Collagen; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D008840:Microfilament Proteins; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000605723:FBN2 protein, human; C000605724:Fbn1 protein, mouse; C000605728:Fbn2 protein, mouse; C479466:Sp7 protein, mouse