Bone regeneration is a complex event that requires the interaction of numerous growth factors. Fibroblast growth factor (Fgf)-ligands have been previously described for their importance in osteogenesis during development. In the current study, we investigated the role of Fgf-18 during bone regeneration. By utilizing a unicortical tibial defect model, we revealed that mice haploinsufficient for Fgf-18 have a markedly reduced healing capacity as compared with wild-type mice. Reduced levels of Runx2 and Osteocalcin but not Vegfa accompanied the impaired bone regeneration. Interestingly, our data indicated that upon injury angiogenesis was not impaired in Fgf-18+/− mice. Moreover, other Fgf-ligands and Bmp-2 could not compensate for the loss of Fgf-18. Finally, application of FGF-18 protein was able to rescue the impaired healing in Fgf-18+/− mice. Thus, we identified Fgf-18 as an important mediator of bone regeneration, which is required during later stages of bone regeneration. This study provides hints on how to engineering efficiently programmed bony tissue for long bone repair.
Get full access to this article
View all access options for this article.
References
1.
SchindelerA., McDonaldM.M., BokkoP., LittleD.G.Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol, 19:459. 2008.
2.
GerstenfeldL.C., CullinaneD.M., BarnesG.L., GravesD.T., EinhornT.A.Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem, 88:873. 2003.
3.
MonteroA., OkadaY., TomitaM., ItoM., TsurukamiH., NakamuraT.et al.Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. J Clin Invest, 105:1085. 2000.
4.
HungI.H., YuK., LavineK.J., OrnitzD.M.FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol, 307:300. 2007.
5.
OhbayashiN., ShibayamaM., KurotakiY., ImanishiM., FujimoriT., ItohN.et al.FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev, 16:870. 2002.
6.
LiuZ., XuJ., ColvinJ.S., OrnitzD.M.Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev, 16:859. 2002.
JabsE.W., LiX., ScottA.F., MeyersG., ChenW., EcclesM.et al.Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2. Nat Genet, 8:275. 1994.
9.
BellusG.A., GaudenzK., ZackaiE.H., ClarkeL.A., SzaboJ., FrancomanoC.A.et al.Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet, 14:174. 1996.
10.
WilkieA.O.Craniosynostosis: genes and mechanisms. Hum Mol Genet, 6:1647. 1997.
11.
ShiangR., ThompsonL.M., ZhuY.Z., ChurchD.M., FielderT.J., BocianM.et al.Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell, 78:335. 1994.
12.
RousseauF.Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature, 371:252. 1994.
13.
BellusG.A., McIntoshI., SmithE.A., AylsworthA.S., KaitilaI., HortonW.A.et al.A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet, 10:357. 1995.
14.
SchmidG.J., KobayashiC., SandellL.J., OrnitzD.M.Fibroblast growth factor expression during skeletal fracture healing in mice. Dev Dyn, 238:766. 2009.
15.
BehrB., LeuchtP., LongakerM.T., QuartoN.Fgf-9 is required for angiogenesis and osteogenesis in long bone repair. Proc Natl Acad Sci U S A, 107:11853. 2010.
16.
HinoiE., BialekP., ChenY.T., RachedM.T., GronerY., BehringerR.R.et al.Runx2 inhibits chondrocyte proliferation and hypertrophy through its expression in the perichondrium. Genes Dev, 20:2937. 2006.
17.
HuM.C., QiuW.R., WangY.P., HillD., RingB.D., ScullyS.et al.FGF-18, a novel member of the fibroblast growth factor family, stimulates hepatic and intestinal proliferation. Mol Cell Biol, 18:6063. 1998.
18.
OhbayashiN., HoshikawaM., KimuraS., YamasakiM., FukuiS., ItohN.Structure and expression of the mRNA encoding a novel fibroblast growth factor, FGF-18. J Biol Chem, 273:18161. 1998.
19.
ReinholdM.I., NaskiM.C.Direct interactions of Runx2 and canonical Wnt signaling induce FGF18. J Biol Chem, 282:3653. 2007.
20.
BollandB.J., KanczlerJ.M., DunlopD.G., OreffoR.O.Development of in vivo muCT evaluation of neovascularisation in tissue engineered bone constructs. Bone, 43:195. 2008.
21.
QuartoN., LongakerM.T.FGF-2 inhibits osteogenesis in mouse adipose tissue-derived stromal cells and sustains their proliferative and osteogenic potential state. Tissue Eng, 12:1405. 2006.
22.
StreetJ., BaoM., deGuzmanL., BuntingS., PealeF.V.Jr., FerraraN.et al.Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A, 99:9656. 2002.
23.
XiaoL., NaganawaT., ObugundeE., GronowiczG., OrnitzD.M., CoffinJ.D.et al.Stat1 controls postnatal bone formation by regulating fibroblast growth factor signaling in osteoblasts. J Biol Chem, 279:27743. 2004.
ShimoakaT., OgasawaraT., YonamineA., ChikazuD., KawanoH., NakamuraK.et al.Regulation of osteoblast, chondrocyte, and osteoclast functions by fibroblast growth factor (FGF)-18 in comparison with FGF-2 and FGF-10. J Biol Chem, 277:7493. 2002.
26.
CanalisE., CentrellaM., McCarthyT.Effects of basic fibroblast growth factor on bone formation in vitro. J Clin Invest, 81:1572. 1988.
27.
MansukhaniA., BellostaP., SahniM., BasilicoC.Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. J Cell Biol, 149:1297. 2000.
28.
NagaiH., TsukudaR., MayaharaH.Effects of basic fibroblast growth factor (bFGF) on bone formation in growing rats. Bone, 16:367. 1995.
29.
BehrB., PanettaN.J., LongakerM.T., QuartoN.Different endogenous threshold levels of Fibroblast Growth Factor-ligands determine the healing potential of frontal and parietal bones. Bone, 47:281. 2010.
