Disruption of the Fgf2 gene activates the adipogenic and suppresses the osteogenic program in mesenchymal marrow stromal stem cells.
Here we determine the Fibroblast Growth Factor-2 (FGF2) dependency of the time course of changes in bone mass in female mice. This study extends our earlier reports that knockout of the FGF2 gene (Fgf2) caused low turnover bone loss in Fgf2(-/-) male mice by examining bone loss with age in Fgf2(-/-) female mice, and by assessing whether reduced bone formation is associated with differentiation of bone marrow stromal cells (BMSCs) towards the adipocyte lineage. Bone mineral density (BMD) was similar in 3-month-old female Fgf2(+/+) and Fgf2(-/-) mice but was significantly reduced as early as 5 months of age in Fgf2(-/-) mice. In vivo studies showed that there was a greater accumulation of marrow fat in long bones of 14 and 20 month old Fgf2(-/-) mice compared with Fgf2(+/+) littermates. To study the effect of disruption of FGF2 on osteoblastogenesis and adipogenesis, BMSCs from both genotypes were cultured in osteogenic or adipogenic media. Reduced alkaline phosphatase positive (ALP), mineralized colonies and a marked increase in adipocytes were observed in Fgf2(-/-) BMSC cultures. These cultures also showed an increase in the mRNA of the adipogenic transcription factor PPARgamma2 as well as the downstream target genes aP2 and adiponectin. Treatment with exogenous FGF2 blocked adipocyte formation and increased ALP colony formation and ALP activity in BMSC cultures of both genotypes. These results support an important role for endogenous FGF2 in osteoblast (OB) lineage determination. Alteration in FGF2 signaling may contribute to impaired OB bone formation capacity and to increased bone marrow fat accumulation both of which are characteristics of aged bone.
Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.
Liping
L
Xiao
Takanori
T
Sobue
Alycia
A
Esliger
Mark S
MS
Kronenberg
J Douglas
JD
Coffin
Thomas
T
Doetschman
Marja M
MM
Hurley
D015502:Absorptiometry, Photon; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics*; D000375:Aging / Q000187:drug effects; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000172:deficiency / Q000235:genetics* / Q000494:pharmacology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D016222:Fibroblast Growth Factor 2