Skip to main content
Download PDF
Download ePub

Role of fibroblast growth factors in bone regeneration

Inflammation and Regeneration volume 37, Article number: 10 (2017) Cite this article

Abstract

Bone is a metabolically active organ that undergoes continuous remodeling throughout life. However, many complex skeletal defects such as large traumatic bone defects or extensive bone loss after tumor resection may cause failure of bone healing. Effective therapies for these conditions typically employ combinations of cells, scaffolds, and bioactive factors. In this review, we pay attention to one of the three factors required for regeneration of bone, bioactive factors, especially the fibroblast growth factor (FGF) family. This family is composed of 22 members and associated with various biological functions including skeletal formation. Based on the phenotypes of genetically modified mice and spatio-temporal expression levels during bone fracture healing, FGF2, FGF9, and FGF18 are regarded as possible candidates useful for bone regeneration. The role of these candidate FGFs in bone regeneration is also discussed in this review.

Background

Tissue engineering is an interdisciplinary field of research and clinical applications, which focuses on restoration of impaired function and morphology of tissues and organs by repair, replacement, or regeneration. It uses a combination of several technological approaches beyond traditional transplantation and replacement therapies. The key components of these approaches are using of cells, scaffolds, and bioactive factors.

Bone is a specialized connective tissue that is being continuously remodeled throughout life. However, many complex clinical conditions such as large traumatic bone defects, osteomyelitis, tumor resection, or skeletal abnormalities can impair normal bone healing. Bone tissue engineering is required for regenerating tissue from these conditions. Studies on the mechanisms of physiological, pathological skeletal development and fracture healing have provided a wealth of information towards potential methods for regulating osteoblast proliferation and differentiation to regenerate bone.

Here, we focus on one of the main components of tissue engineering, bioactive factors, especially fibroblast growth factors (FGFs) and their roles in bone regeneration.

FGF signaling in skeletal formation has been demonstrated by identification of gain-of-function mutations in human FGF receptor (FGFR) genes in craniosynostosis and dwarfism patients and skeletal phenotypes in genetically modified mice for FGFs and FGFRs [1]. FGFRs are transmembrane tyrosine kinase receptors that belong to the immunoglobulin (Ig) superfamily consisting of extracellular, transmembrane, and intracellular tyrosine kinase domains. Binding of FGFs to FGFRs activates intracellular downstream signaling pathways such as RAS-MAP and PI3K-AKT [2]. The FGFR family consists of four members, FGFR1 to FGFR4. Among the four FGFRs, skeletal mutations have been found in FGFRs1–3 expressed in the osteoblast cell lineage. Most of the mutations are point mutations, and distinct mutation sites result in different syndromes [1]. Some of the mutations have been introduced into mice and confirmed to affect skeletal development.

FGFs and bone regeneration

The mammalian FGF family contains 22 members. Some of them are intracellular FGFs (iFGFs), FGFs 11–14, which are expected to function without binding to FGFRs. FGF19 (FGF15 for mice), FGF21, and FGF23 are hormone-like FGFs which act in an endocrine manner in postnatal life. All other FGFs have high affinity to heparin and act in a paracrine manner by binding to the four receptors with different levels of affinities [3,4,5]. The roles of various FGFs are compiled in Table 1. Skeletal phenotypes after deletion of FGFs in mice are found in FGFs 2, 8, 9, 10, 18, and 23 [6], which confirm the indispensable function of FGF/FGFR signaling in the process of osteogenesis. It is of note that FGF/FGFR signaling does not directly induce osteoblast differentiation but is known to modulate osteoblast differentiation. However, the exact mechanism of FGF/FGFR signaling in bone healing or regeneration has not been elucidated. Schmid et al. [7] reported expression levels of different FGFs by reverse transcriptase polymerase chain reaction (RT-PCR) during normal healing of tibial fracture in mice. Throughout the healing process, FGFs 2, 5, and 6 were upregulated with different levels. FGF9 was highly expressed at the early stage of healing. FGFs 16 and 18 were transcribed at the late stage. Upregulation of FGFs 1 and 17 was delayed after callus formation. This study also identified concordance between the expression of the particular FGFs and their known receptors during different stages of fracture repair. Among three FGFRs expressed in the osteoblast cell lineage, FGFR3 showed the greatest change in expression levels. This study provided the idea of how FGFs work at the different stages of healing, which could be applied to bone regenerative therapy.

Table 1 List of FGFs and their various functions
Full size table

Considering clinical applications, studies involving modification of FGF signaling by ligands are more practical compared to those involving modulating FGFRs. Animal studies revealed that the expression of FGFs 8 and 10 is required for the early stage of limb development, which suggests that they are not directly involved in osteogenesis. Among FGFs which change their expression levels during bone fracture healing, FGF1 protects the osteoblast cell lineage from cell death [8]. FGF5 is associated with the hair follicle cycle. FGF6 is involved in muscle regeneration and those events that occur during the healing process. Therefore, in this review, we chose FGFs 2, 9, and 18 to discuss about their properties and applications for bone regeneration.

FGF2

FGF2 is the most common FGF ligand that is being used in the regenerative medicine field including bone regeneration. It has been well known that FGF2 is a critical component of maintenance of many kinds of stem cell cultures [9]. Stabilization of FGF2 levels in a culture medium using polyesters of glycolic and lactic acid (PLGA) microspheres as a FGF2 release controller successfully improved the expression of stem cell markers, increased stem cell numbers, and decreased spontaneous differentiation [10].

FGF2-deleted mice showed a significant decrease in bone mass and bone formation without gross abnormalities. Bone marrow stromal cells (BMSCs) from the FGF2 −/− mice demonstrated decreased osteoblast differentiation, which can be partially rescued by addition of exogenous FGF2 in vitro [11]. Furthermore, FGF2 −/− BMSC-derived osteoblasts displayed a marked reduction in inactive phosphorylated glycogen synthase kinase-3 (GSK-3) as well as a significant decrease in Dkk2 mRNA, which plays important roles in osteoblast differentiation. These results suggested that FGF2 is an endogenous, positive regulator of bone mass [12]. In contrast, non-specific overexpression of FGF2 (Tg-FGF2) in mice exhibits a dwarf phenotype with impaired bone mineralization and osteopenia [13]. Addition of FGF2 into a culture medium of a mouse osteoblast-like cell line, MC3T3-E1, activated cell proliferation and suppressed mineralization [14]. In this study, treatment of the cells with FGF10 as an experimental control did not show any effects. These observations suggested that FGF2 could work in both directions for osteogenesis promotion and inhibition. It is important to elucidate conditions for positive and negative osteogeneses.

FGF9

FGF9 −/− mice showed disproportionate shortening of the proximal skeletal elements (rhizomelia), which suggests that FGF9 promotes chondrocyte hypertrophy and vascularization of the cartilage anlagen [15]. A missense mutation of FGF9 in mice resulted in decreased heparin binding, which caused elbow-knee synostosis [16]. A similar mutation was also found in humans [17]. FGF9 +/− mice did not seem to have a particular phenotype. However, bone healing of a 1-mm unicortical defect was impaired with decreased levels of neovascularization and osteoclast recruitment. This condition was rescued by exogenous addition of FGF9 (2 μg) with collagen sponge but not by exogenous FGF2 application [18]. These reports elucidated the specific functions of FGF9 in bone healing.

Bone healing of a 1-mm unicortical defect in diabetic model mice (db/db) was significantly delayed with decreased levels of osteogenesis marker expressions. Treatment of FGF9 with collagen sponge to the defect in the db/db mice induced better bone healing [19]. Treatment with FGF9-soaked collagen sponge to mouse circular calvarial bone defects of a diameter of 2 mm showed sufficient bone regeneration in postnatal day 7 (P7) mice but not in postnatal day 60 (P60) mice [20]. Addition of FGF9 with various concentrations into dexamethasone-containing media for inducing osteogenesis of BMSCs and dental pulp stem cells resulted in stimulation of proliferation but not differentiation [21].

FGF18

Deletion of FGF18 in mice resulted in delayed suture formation, reduced osteoblast lineage cell proliferation, delayed osteoblast differentiation, and perinatal death. The long bones of FGF18 −/− mice showed reduced osteoblast differentiation but increased chondrocyte proliferation and differentiation. These results suggested that FGF18 demonstrated a positive effect on osteogenesis by enhancing cell proliferation and differentiation but a negative effect on chondrogenesis [22, 23]. However, it was also proposed that FGF18 transduced the signal through FGFR3 to enhance cartilage formation [24].

In vitro analysis on mesenchymal stem cells (MSCs) derived from the bone marrow suggested that FGF18 enhanced osteoblast differentiation by activation of FGFR1 or FGFR2 signaling [25]. They also showed that overexpression of FGF18 by lentiviral infection or direct addition of FGF18 into the culture medium could induce the expression of osteoblast marker genes in C3H10T1/2 fibroblastic cells. Treatment of FGF18 on rat-derived MSCs under a differentiation-inducing condition showed elevated expression of osteoblast differentiation markers and mineralization [26]. Low-dose FGF18 treatment with bone morphogenetic protein 2 (BMP2)-dependent osteogenic induction of MC3T3-E1 cells enhanced mineralization whereas high-dose treatment inhibited the process (unpublished observation of Sachiko Iseki). FGF18-soaked heparin-coated acrylic beads accelerated osteoblast differentiation in mouse fetuses by upregulating the expression of BMP2 in osteoblast cell lineage cells [27]. In accordance with the above reports, FGF18 application with BMP2 in cholesteryl group- and acryloyl group-bearing pullulan (CHPOA) nanogels stabilized BMP2-dependent bone regeneration of critical-sized bone defects on mouse calvarium [28].

Application of FGFs in bone regeneration

The above discussions suggest that although FGFs do not have osteoinductive property, they function as an accelerator of osteogenesis under the appropriate conditions. It is possible that FGF2 and FGF9 work on proliferation of osteoblast cell lineage as well as induction of angiogenesis, and FGF18 functions in promotion of osteoblast differentiation. Tables 2 and 3 show some of the in vivo experiments in which FGFs were applied to non-critical- and critical-sized bone defects for bone healing, respectively. Further applications of FGFs have been elaborated by Du et al. and Gothard et al. [29, 30].

Table 2 Application of different FGFs in non-critical-sized bone defect in vivo models
Full size table
Table 3 Application of different FGFs in critical-sized bone defect in vivo models
Full size table

Systemic or subcutaneous injections of FGF2 could enhance osteogenesis. However, it was shown that systemic injections of FGF2 caused adverse extraskeletal effects [31]. Therefore, local administration has been chosen as a more preferable method for applying bioactive factors. FGF2 has been used for inducing angiogenesis and enhancing osteogenesis in non-critical-sized bone defects by activating proliferation of osteoblast cell lineages. FGF9 is also suggested to be involved in angiogenesis by controlling VEGFa expression [18]. As long as osteogenesis is taking place to recover the bone defect, FGF2 can support or even enhance the healing. Recent studies suggest that high-dose FGF2 inhibits progression of osteoblast differentiation [20, 32, 33] (also unpublished observation of Sachiko Iseki) and low concentration of FGF2 enhanced osteogenesis [33, 34]. In contrast, it is likely that high-dose FGF18 can promote osteoblast differentiation in vivo [20, 28], while FGF18 treatment in vitro inhibits mineralization [14].

Kang et al. developed a sequential delivery system with fiber scaffolds in which FGF2 was released first and then FGF18 [35]. Applying this scaffold to rat calvarial critical-sized bone defects resulted in better bone volume and density, although the amount of FGFs applied to the defect was not clear. This study suggested that it is critical to control the amount or release speed of soluble factors for the bone regeneration process.

Conclusions

FGFs play an important role in the development and regeneration of various tissues. In this article, we have summarized the prime functions of all FGFs, and further, we have discussed elaborately about FGFs 2, 9 and 18, which play a major role in bone regeneration. We have also discussed about different carrier systems for FGF delivery in different animal models for bone regeneration. With the ongoing advancements in the field of cellular and molecular biology, we could expect that more detailed functioning of FGF/FGFR will be elucidated. Further, with the advent of novel carriers and protein delivery systems, it could be possible that the spatio-temporal release of FGFs can be controlled precisely as needed. This would improve our understanding and help us to clinically translate the use of FGFs to achieve effective bone regeneration.

Abbreviations

BMP2:

Bone morphogenetic protein 2

BMSC:

Bone marrow stromal cells

CHPOA:

Cholesteryl group- and acryloyl group-bearing pullulan

Col-HA/PEG:

Collagen-hydroxyapatite/polyethylene glycol

Dkk2:

Dickkopf-related protein 2

FGF:

Fibroblast growth factor

FGFR:

Fibroblast growth factor receptor

GSK-3:

Glycogen synthase kinase-3

iFGF:

Intracellular fibroblast growth factor

Ig:

Immunoglobulin

MSC:

Mesenchymal stem cells

PLGA:

Polyesters of glycolic and lactic acid

RT-PCR:

Reverse transcriptase polymerase chain reaction

Tg-FGF2:

Transgenic fibroblast growth factor 2

VEGFa:

Vascular endothelial growth factor A

β-TCP:

Beta tricalcium phosphate

References

  1. Wilkie AO. Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine Growth Factor Rev. 2005;16:187–203.

    Article  CAS  PubMed  Google Scholar 

  2. Goetz R, Mohammadi M. Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol. 2013;14:166–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Itoh N, Ornitz DM. Functional evolutionary history of the mouse Fgf gene family. Dev Dyn. 2008;237:18–27.

    Article  CAS  PubMed  Google Scholar 

  4. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, et al. Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996;271:15292–7.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006;281:15694–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Itoh N. The Fgf families in humans, mice, and zebrafish: their evolutional processes and roles in development, metabolism, and disease. Biol Pharm Bull. 2007;30:1819–25.

    Article  CAS  PubMed  Google Scholar 

  7. Schmid GJ, Kobayashi C, Sandell LJ, Ornitz DM. Fibroblast growth factor expression during skeletal fracture healing in mice. Dev Dyn. 2009;238:766–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kelpke S, Reiff D, Prince C, Thompson J. Acidic fibroblast growth factor signaling inhibits peroxynitrite‐induced death of osteoblasts and osteoblast precursors. J Bone Miner Res. 2001;16:1917–25.

    Article  CAS  PubMed  Google Scholar 

  9. Levenstein ME, Ludwig TE, Xu RH, Llanas RA, VanDenHeuvel‐Kramer K, Manning D, et al. Basic fibroblast growth factor support of human embryonic stem cell self‐renewal. Stem Cells. 2006;24:568–74.

    Article  CAS  PubMed  Google Scholar 

  10. Lotz S, Goderie S, Tokas N, Hirsch SE, Ahmad F, Corneo B, et al. Sustained levels of FGF2 maintain undifferentiated stem cell cultures with biweekly feeding. PLoS One. 2013;8:e56289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Montero A, Okada Y, Tomita M, Ito M, Tsurukami H, Nakamura T, et al. Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. J Clin Invest. 2000;105:1085–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fei Y, Xiao L, Doetschman T, Coffin DJ, Hurley MM. Fibroblast growth factor 2 stimulation of osteoblast differentiation and bone formation is mediated by modulation of the Wnt signaling pathway. J Biol Chem. 2011;286:40575–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Coffin J, Florkiewicz R, Neumann J, Mort-Hopkins T, Gn D, Lightfoot P, et al. Abnormal bone growth and selective translational regulation in basic fibroblast growth factor (FGF-2) transgenic mice. Mol Biol Cell. 1995;6:1861–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shimoaka T, Ogasawara T, Yonamine A, Chikazu D, Kawano H, Nakamura K, 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. 2002;277:7493–500.

    Article  CAS  PubMed  Google Scholar 

  15. Hung IH, Yu K, Lavine KJ, Ornitz DM. FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol. 2007;307:300–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Harada M, Murakami H, Okawa A, Okimoto N, Hiraoka S, Nakahara T, et al. FGF9 monomer–dimer equilibrium regulates extracellular matrix affinity and tissue diffusion. Nat Genet. 2009;41:289–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu X-l, Gu M-m, Huang L, Liu X-s, Zhang H-x, Ding X-y, et al. Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene. Am J Hum Genet. 2009;85:53–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Behr B, Leucht P, Longaker MT, Quarto N. Fgf9 is required for angiogenesis and osteogenesis in long bone repair. Proc Natl Acad Sci U S A. 2010;107:11853–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wallner C, Schira J, Wagner JM, Schulte M, Fischer S, Hirsch T, et al. Application of VEGFA and FGF9 enhances angiogenesis, osteogenesis and bone remodeling in type 2 diabetic long bone regeneration. PLoS One. 2015;10:e0118823.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Behr B, Panetta NJ, Longaker MT, Quarto N. Different endogenous threshold levels of fibroblast growth factor-ligands determine the healing potential of frontal and parietal bones. Bone. 2010;47:281–94.

    Article  CAS  PubMed  Google Scholar 

  21. Lu J, Dai J, Wang X, Zhang M, Zhang P, Sun H, et al. Effect of fibroblast growth factor 9 on the osteogenic differentiation of bone marrow stromal stem cells and dental pulp stem cells. Mol Med Rep. 2015;11:1661–8.

    CAS  PubMed  Google Scholar 

  22. Ohbayashi N, Shibayama M, Kurotaki Y, Imanishi M, Fujimori T, Itoh N, et al. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev. 2002;16:870–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu Z, Xu J, Colvin JS, Ornitz DM. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev. 2002;16:859–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Davidson D, Blanc A, Filion D, Wang H, Plut P, Pfeffer G, et al. Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J BiolChem. 2005;280:20509–15.

    CAS  Google Scholar 

  25. Hamidouche Z, Fromigué O, Nuber U, Vaudin P, Ebert R, Jakob F, et al. Autocrine fibroblast growth factor 18 mediates dexamethasone‐induced osteogenic differentiation of murine mesenchymal stem cells. J Cell Physiol. 2010;224:509–15.

    Article  CAS  PubMed  Google Scholar 

  26. Jeon E, Yun Y-R, Kang W, Lee S, Koh Y-H, Kim H-W, et al. Investigating the role of FGF18 in the cultivation and osteogenic differentiation of mesenchymal stem cells. PLoS One. 2012;7:e43982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nagayama T, Okuhara S, Ota MS, Tachikawa N, Kasugai S, Iseki S. FGF18 accelerates osteoblast differentiation by upregulating Bmp2 expression. Congenit Anom. 2013;53:83–8.

    Article  CAS  Google Scholar 

  28. Fujioka-Kobayashi M, Ota MS, Shimoda A, Nakahama K-I, Akiyoshi K, Miyamoto Y, et al. Cholesteryl group- and acryloyl group-bearing pullulan nanogel to deliver BMP2 and FGF18 for bone tissue engineering. Biomaterials. 2012;33:7613–20.

    Article  CAS  PubMed  Google Scholar 

  29. Du X, Xie Y, Xian CJ, Chen L. Role of FGFs/FGFRs in skeletal development and bone regeneration. J Cell Physiol. 2012;227:3731–43.

    Article  CAS  PubMed  Google Scholar 

  30. Gothard D, Smith E, Kanczler J, Rashidi H, Qutachi O, Henstock J, et al. Tissue engineered bone using select growth factors: a comprehensive review of animal studies and clinical translation studies in man. Eur Cell Mater. 2014;28:166–208.

    Article  CAS  PubMed  Google Scholar 

  31. Wamsley HL, Iwaniec UT, Wronski TJ. Selected extraskeletal effects of systemic treatment with basic fibroblast growth factor in ovariectomized rats. Toxicol Pathol. 2005;33:577–83.

    Article  CAS  PubMed  Google Scholar 

  32. Mabilleau G, Aguado E, Stancu IC, Cincu C, Baslé MF, Chappard D. Effects of FGF-2 release from a hydrogel polymer on bone mass and microarchitecture. Biomaterials. 2008;29:1593–600.

    Article  CAS  PubMed  Google Scholar 

  33. Nakamura Y, Tensho K, Nakaya H, Nawata M, Okabe T, Wakitani S. Low dose fibroblast growth factor-2 (FGF-2) enhances bone morphogenetic protein-2 (BMP-2)-induced ectopic bone formation in mice. Bone. 2005;36:399–407.

    Article  CAS  PubMed  Google Scholar 

  34. Charles LF, Woodman JL, Ueno D, Gronowicz G, Hurley MM, Kuhn LT. Effects of low dose FGF-2 and BMP-2 on healing of calvarial defects in old mice. Exp Geront. 2015;64:62–9.

    Article  CAS  Google Scholar 

  35. Kang MS, Kim J-H, Singh RK, Jang J-H, Kim H-W. Therapeutic-designed electrospun bone scaffolds: mesoporous bioactive nanocarriers in hollow fiber composites to sequentially deliver dual growth factors. Acta Biomater. 2015;16:103–16.

    Article  CAS  PubMed  Google Scholar 

  36. Hyer J, Mima T, Mikawa T. FGF1 patterns the optic vesicle by directing the placement of the neural retina domain. Development. 1998;125:869–77.

    CAS  PubMed  Google Scholar 

  37. Dono R, Texido G, Dussel R, Ehmke H, Zeller R. Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice. EMBO J. 1998;17:4213–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou M, Sutliff RL, Paul RJ, Lorenz JN, Hoying JB, Haudenschild CC, et al. Fibroblast growth factor 2 control of vascular tone. Nat Med. 1998;4:201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Van Gastel N, Stegen S, Van Looveren R, Stockmans I, Schrooten J, Graf D, et al. FGF2 primes periosteal cells for endochondral ossification via maintenance of skeletal precursors and modulation of BMP signaling. 35th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR); Baltimore, Maryland, USA 2013.

  40. Feldman B, Poueymirou W, Papaioannou VE, DeChiara TM, Goldfarb M. Requirement of FGF-4 for postimplantation mouse development. Science. 1995;267:246.

    Article  CAS  PubMed  Google Scholar 

  41. Hébert JM, Rosenquist T, Götz J, Martin GR. FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations. Cell. 1994;78:1017–25.

    Article  PubMed  Google Scholar 

  42. Armand A-S, Laziz I, Chanoine C. FGF6 in myogenesis. BBA Mol Cell Res. 2006;1763:773–8.

    CAS  Google Scholar 

  43. Maroon H, Walshe J, Mahmood R, Kiefer P, Dickson C, Mason I. Fgf3 and Fgf8 are required together for formation of the otic placode and vesicle. Development. 2002;129:2099–108.

    CAS  PubMed  Google Scholar 

  44. Kettunen P, Laurikkala J, Itäranta P, Vainio S, Itoh N, Thesleff I. Associations of FGF-3 and FGF-10 with signaling networks regulating tooth morphogenesis. Dev Dyn. 2000;219:322–32.

    Article  CAS  PubMed  Google Scholar 

  45. Guo L, Degenstein L, Fuchs E. Keratinocyte growth factor is required for hair development but not for wound healing. Gene Dev. 1996;10:165–75.

    Article  CAS  PubMed  Google Scholar 

  46. Qiao J, Uzzo R, Obara-Ishihara T, Degenstein L, Fuchs E, Herzlinger D. FGF-7 modulates ureteric bud growth and nephron number in the developing kidney. Development. 1999;126:547–54.

    CAS  PubMed  Google Scholar 

  47. Sekine K, Ohuchi H, Fujiwara M, Yamasaki M, Yoshizawa T, Sato T, et al. Fgf10 is essential for limb and lung formation. Nat Genet. 1999;21:138–41.

    Article  CAS  PubMed  Google Scholar 

  48. Bhushan A, Itoh N, Kato S, Thiery JP, Czernichow P, Bellusci S, et al. Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis. Development. 2001;128:5109–17.

    CAS  PubMed  Google Scholar 

  49. Umemori H, Linhoff MW, Ornitz DM, Sanes JR. FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell. 2004;118:257–70.

    Article  CAS  PubMed  Google Scholar 

  50. Nakatake Y, Hoshikawa M, Asaki T, Kassai Y, Itoh N. Identification of a novel fibroblast growth factor, FGF-22, preferentially expressed in the inner root sheath of the hair follicle. BBA Gene Struct Expr. 2001;1517:460–3.

    Article  CAS  Google Scholar 

  51. Colvin JS, White AC, Pratt SJ, Ornitz DM. Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development. 2001;128:2095–106.

    CAS  PubMed  Google Scholar 

  52. Barak H, Huh S-H, Chen S, Jeanpierre C, Martinovic J, Parisot M, et al. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev Cell. 2012;22:1191–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier M-C, et al. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biol. 2006;4:e187.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lu SY, Sheikh F, Sheppard PC, Fresnoza A, Duckworth ML, Detillieux KA, et al. FGF-16 is required for embryonic heart development. Biochem Biophys Res Commun. 2008;373:270–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hayashi T, Ray CA, Bermingham-McDonogh O. Fgf20 is required for sensory epithelial specification in the developing cochlea. J Neurosci. 2008;28:5991–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Reifers F, Bohli H, Walsh EC, Crossley PH, Stainier D, Brand M. Fgf8 is mutated in zebrafish acerebellar (ace) mutants and is required for maintenance of midbrain-hindbrain boundary development and somitogenesis. Development. 1998;125:2381–95.

    CAS  PubMed  Google Scholar 

  57. Crossley PH, Minowada G, MacArthur CA, Martin GR. Roles for FGF8 in the induction, initiation, and maintenance of chick limb development. Cell. 1996;84:127–36.

    Article  CAS  PubMed  Google Scholar 

  58. Abu-Issa R, Smyth G, Smoak I, Yamamura K-i, Meyers EN. Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development. 2002;129:4613–25.

    CAS  PubMed  Google Scholar 

  59. Albertson RC, Yelick PC. Roles for fgf8 signaling in left–right patterning of the visceral organs and craniofacial skeleton. Dev Biol. 2005;283:310–21.

    Article  CAS  PubMed  Google Scholar 

  60. Cholfin JA, Rubenstein JL. Patterning of frontal cortex subdivisions by Fgf17. Proc Natl Acad Sci U S A. 2007;104:7652–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Usui H, Shibayama M, Ohbayashi N, Konishi M, Takada S, Itoh N. Fgf18 is required for embryonic lung alveolar development. Biochem Biophys Res Commun. 2004;322:887–92.

    Article  CAS  PubMed  Google Scholar 

  62. Kettunen P, Furmanek T, Chaulagain R, Hals Kvinnsland I, Luukko K. Developmentally regulated expression of intracellular Fgf11-13, hormone-like Fgf15 and canonical Fgf16, -17 and -20 mRNAs in the developing mouse molar tooth. Acta Odontol Scand. 2011;69:360–6.

    Article  CAS  PubMed  Google Scholar 

  63. Zhang X, Bao L, Yang L, Wu Q, Li S. Roles of intracellular fibroblast growth factors in neural development and functions. Sci China Life Sci. 2012;55:1038–44.

    Article  CAS  PubMed  Google Scholar 

  64. Potthoff MJ, Boney-Montoya J, Choi M, He T, Sunny NE, Satapati S, et al. FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway. Cell Metab. 2011;13:729–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, Maratos-Flier E. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes. 2010;59:2781–9.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest. 2004;113:561–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kawaguchi H, Nakamura K, Tabata Y, Ikada Y, Aoyama I, Anzai J, et al. Acceleration of fracture healing in nonhuman primates by fibroblast growth factor-2. J Clin Endocrinol Metab. 2001;86:875–80.

    Article  CAS  PubMed  Google Scholar 

  68. Oortgiesen DA, Walboomers XF, Bronckers AL, Meijer GJ, Jansen JA. Periodontal regeneration using an injectable bone cement combined with BMP-2 or FGF-2. J Tissue Eng Regen Med. 2014;8:202–9.

    Article  CAS  PubMed  Google Scholar 

  69. Yoshida T, Miyaji H, Otani K, Inoue K, Nakane K, Nishimura H, et al. Bone augmentation using a highly porous PLGA/β-TCP scaffold containing fibroblast growth factor-2. J Periodont Res. 2015;50:265–73.

    Article  CAS  PubMed  Google Scholar 

  70. Hong KS, Kim EC, Bang SH, Chung CH, Lee YI, Hyun JK, et al. Bone regeneration by bioactive hybrid membrane containing FGF2 within rat calvarium. J Biomed Mater Res A. 2010;94:1187–94.

    PubMed  Google Scholar 

  71. Takechi M, Tatehara S, Satomura K, Fujisawa K, Nagayama M. Effect of FGF-2 and melatonin on implant bone healing: a histomorphometric study. J Mater Sci Mater Med. 2008;19:2949–52.

    Article  CAS  PubMed  Google Scholar 

  72. Kawaguchi H, Jingushi S, Izumi T, Fukunaga M, Matsushita T, Nakamura T, et al. Local application of recombinant human fibroblast growth factor-2 on bone repair: a dose-escalation prospective trial on patients with osteotomy. J Orthop Res. 2007;25:480–7.

    Article  CAS  PubMed  Google Scholar 

  73. Nakasa T, Ishida O, Sunagawa T, Nakamae A, Yokota K, Adachi N, et al. Feasibility of prefabricated vascularized bone graft using the combination of FGF-2 and vascular bundle implantation within hydroxyapatite for osteointegration. J Biomed Mater Res A. 2008;85:1090–5.

    Article  PubMed  Google Scholar 

  74. Tanaka E, Ishino Y, Sasaki A, Hasegawa T, Watanabe M, Dalla-Bona DA, et al. Fibroblast growth factor-2 augments recombinant human bone morphogenetic protein-2-induced osteoinductive activity. Ann Biomed Eng. 2006;34:717–25.

    Article  PubMed  Google Scholar 

  75. Zellin G, Linde A. Effects of recombinant human fibroblast growth factor-2 on osteogenic cell populations during orthopic osteogenesis in vivo. Bone. 2000;26:161–8.

    Article  CAS  PubMed  Google Scholar 

  76. Ishii Y, Fujita T, Okubo N, Ota M, Yamada S, Saito A. Effect of basic fibroblast growth factor (FGF-2) in combination with beta tricalcium phosphate on root coverage in dog. Acta Odontol Scand. 2013;71:325–32.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to express our sincere gratitude to all the researchers, collaborators, technical assistants, and secretaries for contributing to the research cited in the present manuscript.

Funding

Not applicable.

Availability of data and materials

Not applicable.

Authors’ contributions

All authors contributed equally to drafting the manuscript. All authors read, revised, and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author information

Authors and Affiliations

  1. Section of Molecular Craniofacial Embryology, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan

    Pornkawee Charoenlarp, Arun Kumar Rajendran & Sachiko Iseki

Authors
  1. Pornkawee Charoenlarp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arun Kumar Rajendran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sachiko Iseki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sachiko Iseki.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Charoenlarp, P., Rajendran, A.K. & Iseki, S. Role of fibroblast growth factors in bone regeneration. Inflamm Regener 37, 10 (2017). https://doi.org/10.1186/s41232-017-0043-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s41232-017-0043-8

Keywords

Inflammation and Regeneration

ISSN: 1880-8190

Contact us