Exported 18-kDa isoform of fibroblast growth factor-2 is a critical determinant of bone mass in mice.
The role of the 18-kDa isoform of fibroblast growth factor-2 (FGF2) in the maintenance of bone mass was examined in Col3.6-18-kDa FGF2-IRES-GFPsaph transgenic (18-kDa TgFGF2) mice in which a 3.6-kb fragment of the type I collagen 5'-regulatory region (Col3.6) drives the expression of only the 18-kDa isoform of FGF2 with green fluorescent protein-sapphire (GFPsaph). Vector only transgenic mice (Col3.6-IRES-GFPsaph, VTg) were also developed as a control, and mice specifically deficient in 18-kDa FGF2 (FGF2(lmw)(-/-)) were also examined. Bone mineral density, femoral bone volume, trabecular thickness, and cortical bone area and thickness were significantly increased in 18-kDa TgFGF2 mice compared with VTg. Bone marrow cultures (BMSC) from 18-kDa TgFGF2 mice produced more mineralized nodules than VTg. Increased bone formation was associated with reduced expression of the Wnt antagonist secreted frizzled receptor 1 (sFRP-1). In contrast to 18-kDa TgFGF2 mice, FGF2(lmw)(-/-) mice have significantly reduced bone mineral density and fewer mineralized nodules, coincident with increased expression of sFRP-1 in bones and BMSC. Moreover, silencing of sFRP-1 in BMSC from FGF2(lmw)(-/-) mice reversed the decrease in beta-catenin and Runx2 mRNA. Assay of Wnt/beta-catenin-mediated transcription showed increased and decreased TCF-luciferase activity in BMSC from 18-kDa TgFGF2 and FGF2(lmw)(-/-) mice, respectively. Collectively, these results demonstrate that the 18-kDa FGF2 isoform is a critical determinant of bone mass in mice by modulation of the Wnt signaling pathway.
Xiao
Liping
L
Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030.
Liu
Peng
P
Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, Connecticut 06030.
Li
Xiaofeng
X
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8064, BIO5 Institute.
Doetschman
Thomas
T
Department of Cell Biology and Anatomy, University of Arizona, Tucson, Arizona 85724-5217.
Coffin
J Douglas
JD
Department of Biomedical & Pharmaceutical Sciences, the University of Montana, Missoula, Montana 59812-1552.
Drissi
Hicham
H
Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, Connecticut 06030.
Hurley
Marja M
MM
Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030. Electronic address: hurley@exchange.uchc.edu.
D015502:Absorptiometry, Photon; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D015519:Bone Density; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D017931:DNA Primers; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000502:physiology*; D019084:Fluorescent Antibody Technique, Indirect; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics
D024042:Collagen Type I; D017931:DNA Primers; D020033:Protein Isoforms; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2