Fgf-9 is required for angiogenesis and osteogenesis in long bone repair.
Bone healing requires a complex interaction of growth factors that establishes an environment for efficient bone regeneration. Among these, FGFs have been considered important for intrinsic bone-healing capacity. In this study, we analyzed the role of Fgf-9 in long bone repair. One-millimeter unicortical defects were created in tibias of Fgf-9(+/-) and wild-type mice. Histomorphometry revealed that half-dose gene of Fgf-9 markedly reduced bone regeneration as compared with wild-type. Both immunohistochemistry and RT-PCR analysis revealed markedly decreased levels of proliferating cell nuclear antigen (PCNA), Runt-related transcription factor 2 (Runx2), osteocalcin, Vega-a, and platelet endothelial cell adhesion molecule 1 (PECAM-1) in Fgf-9(+/-) defects. muCT angiography indicated dramatic impairment of neovascularization in Fgf-9(+/-) mice as compared with controls. Treatment with FGF-9 protein promoted angiogenesis and successfully rescued the healing capacity of Fgf-9(+/-) mice. Importantly, although other pro-osteogenic factors [Fgf-2, Fgf-18, and bone morphogenic protein 2 (Bmp-2)] still were present in Fgf-9(+/-) mice, they could not compensate for the haploinsufficiency of the Fgf-9 gene. Therefore, endogenous Fgf-9 seems to play an important role in long bone repair. Taken together our data suggest a unique role for Fgf-9 in bone healing, presumably by initiating angiogenesis through Vegf-a. Moreover, this study further supports the embryonic phenotype previously observed in the developing limb, thus promoting the concept that healing processes in adult organisms may recapitulate embryonic skeletal development.
Behr
Björn
B
Children's Surgical Research Program, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Leucht
Philipp
P
Longaker
Michael T
MT
Quarto
Natalina
N
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001861:Bone Regeneration / Q000235:genetics / Q000502:physiology; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013977:Tibia / Q000098:blood supply / Q000187:drug effects / Q000293:injuries / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D015415:Biomarkers; C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse