Stat1 controls postnatal bone formation by regulating fibroblast growth factor signaling in osteoblasts.
Activation of the signal transducers and activators of transcription (STAT) pathway is important in fibroblast growth factor (FGF) modulation of chondrocyte proliferation and endochondral bone formation during embryogenesis. However, it is not known if the FGF/STAT signaling pathway is important for postnatal bone formation. To examine this, we have characterized a novel skeletal phenotype in Stat1-/- mice in which we find a significant increase in bone mineral density, bone mineral content, and other parameters of bone growth. The data show that osteoblasts derived from Stat1-/- mice have decreased expression of cell cycle inhibitor p21WAF/CIP and FGF receptor 3, a known negative regulator of chondrocyte proliferation. Interestingly, Stat1-/- osteoblasts showed increased expression of FGF18 in vivo and increased responsiveness to FGF18 in vitro. These results suggest a mechanism for the regulation of the osteoblast in which Stat1 functions not only to directly regulate the cell cycle but also to modify the repertoire of FGF receptor expression from a potentially inhibitory receptor, FGFR3 to a stimulatory receptor such as FGFR1 or FGFR2.
Xiao
Liping
L
Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030-1850, USA.
Naganawa
Takahiro
T
Obugunde
Eneze
E
Gronowicz
Gloria
G
Ornitz
David M
DM
Coffin
J Douglas
JD
Hurley
Marja M
MM
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015519:Bone Density; D002113:Calcification, Physiologic / Q000502:physiology; D002452:Cell Count; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005269:Femur / Q000000981:diagnostic imaging / Q000254:growth & development / Q000648:ultrastructure; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D012886:Skull / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D013131:Spine / Q000000981:diagnostic imaging / Q000254:growth & development / Q000648:ultrastructure; D013936:Thymidine / Q000008:administration & dosage* / Q000378:metabolism; D014057:Tomography, X-Ray Computed / Q000379:methods; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D017468:Receptors, Fibroblast Growth Factor; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; C113569:fibroblast growth factor 18; D005346:Fibroblast Growth Factors; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D000469:Alkaline Phosphatase; D013936:Thymidine