TY - JOUR
T1 - Exported 18-kDa isoform of fibroblast growth factor-2 is a critical determinant of bone mass in mice
AU - Xiao, Liping
AU - Liu, Peng
AU - Li, Xiaofeng
AU - Doetschman, Thomas
AU - Coffin, J. Douglas
AU - Drissi, Hicham
AU - Hurley, Marja M.
PY - 2009/1/30
Y1 - 2009/1/30
N2 - 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-IRESGFPsaph, VTg) were also developed as a control, and mice specifically deficient in 18-kDa FGF2 (FGF2lmw-/-) 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, FGF2lmw-/- 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 FGF2lmw-/- mice reversed the decrease in β-catenin and Runx2 mRNA. Assay of Wnt/β-catenin- mediated transcription showed increased and decreased TCF-luciferase activity in BMSC from 18-kDa TgFGF2 and FGF2lmw-/- 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.
AB - 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-IRESGFPsaph, VTg) were also developed as a control, and mice specifically deficient in 18-kDa FGF2 (FGF2lmw-/-) 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, FGF2lmw-/- 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 FGF2lmw-/- mice reversed the decrease in β-catenin and Runx2 mRNA. Assay of Wnt/β-catenin- mediated transcription showed increased and decreased TCF-luciferase activity in BMSC from 18-kDa TgFGF2 and FGF2lmw-/- 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.
UR - http://www.scopus.com/inward/record.url?scp=59149105843&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=59149105843&partnerID=8YFLogxK
U2 - 10.1074/jbc.M804900200
DO - 10.1074/jbc.M804900200
M3 - Article
C2 - 19056741
AN - SCOPUS:59149105843
SN - 0021-9258
VL - 284
SP - 3170
EP - 3182
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 5
ER -