Over-expression of fibroblast growth factor-2 causes defective bone mineralization and osteopenia in transgenic mice.
Over-expression of human FGF-2 cDNA linked to the phosphoglycerate kinase promoter in transgenic (TgFGF2) mice resulted in a dwarf mouse with premature closure of the growth plate and shortening of bone length. This study was designed to further characterize bone structure and remodeling in these mice. Bones of 1-6 month-old wild (NTg) and TgFGF2 mice were studied. FGF-2 protein levels were higher in bones of TgFGF2 mice. Bone mineral density was significantly decreased as early as 1 month in femurs from TgFGF2 mice compared with NTg mice. Micro-CT of trabecular bone of the distal femurs from 6-month-old TgFGF2 mice revealed significant reduction in trabecular bone volume, trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). Osteoblast surface/bone surface, double-labeled surface, mineral apposition rate, and bone formation rates were all significantly reduced in TgFGF2 mice. There were fewer TRAP positive osteoclasts in calvaria from TgFGF2 mice. Quantitative histomorphometry showed that total bone area was similar in both genotypes, however percent osteoclast surface, and osteoclast number/bone surface were significantly reduced in TgFGF2 mice. Increased replication of TgFGF2 calvarial osteoblasts was observed and primary cultures of bone marrow stromal cells from TgFGF2 expressed markers of mature osteoblasts but formed fewer mineralized nodules. The data presented indicate that non-targeted over-expression of FGF-2 protein resulted in decreased endochondral and intramembranous bone formation. These results are consistent with FGF-2 functioning as a negative regulator of postnatal bone growth and remodeling in this animal model.
Sobue
T
T
University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Naganawa
T
T
Xiao
L
L
Okada
Y
Y
Tanaka
Y
Y
Ito
M
M
Okimoto
N
N
Nakamura
T
T
Coffin
J D
JD
Hurley
M M
MM
D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016723:Bone Remodeling / Q000235:genetics; D002113:Calcification, Physiologic / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*
D016222:Fibroblast Growth Factor 2