Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation.
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.
Nistala
Harikiran
H
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10021, USA.
Lee-Arteaga
Sui
S
Smaldone
Silvia
S
Siciliano
Gabriella
G
Carta
Luca
L
Ono
Robert N
RN
Sengle
Gerhard
G
Arteaga-Solis
Emilio
E
Levasseur
Regis
R
Ducy
Patricia
P
Sakai
Lynn Y
LY
Karsenty
Gerard
G
Ramirez
Francesco
F
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
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