Disease relevance of Fgf18

• Here we show that delayed mineralization in Fgf18(-/-) mice was closely associated with delayed initiation of chondrocyte hypertrophy, decreased proliferation at early stages of chondrogenesis, delayed skeletal vascularization and delayed osteoclast and osteoblast recruitment to the growth plate [1].
• Recombinant rat FGF-18, which was efficiently secreted by High Five insect cells infected with recombinant baculovirus containing the cDNA, induced neurite outgrowth in PC12 cells [2].
• With regard to the action of FGF-18 on bone resorption, FGF-18 not only induced osteoclast formation through receptor activator of nuclear factor-kappaB ligand and cyclooxygenase-2 but also stimulated osteoclast function to form resorbed pits on a dentine slice in the mouse coculture system [3].

High impact information on Fgf18

• These data suggest that FGF18 acts as a physiological ligand for FGFR3 [4].
• These data demonstrate that FGF18 signals through another FGFR to regulate osteoblast growth [4].
• In addition, mice lacking Fgf18 display delayed ossification and decreased expression of osteogenic markers, phenotypes not seen in mice lacking Fgfr3 [4].
• Mice lacking either Fgf18 or Fgfr3 exhibited expanded zones of proliferating and hypertrophic chondrocytes and increased chondrocyte proliferation, differentiation, and Indian hedgehog signaling [4].
• Signaling to multiple FGFRs positions FGF18 to coordinate chondrogenesis in the growth plate with osteogenesis in cortical and trabecular bone [4].

Biological context of Fgf18

• Finally, brain explants were used to define a positive feedback loop involving FGF8b mediated upregulation of Fgf18, and two negative feedback loops that include repression of Fgfr2/3 and direct induction of Spry1/2 [5].
• Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18 [4].
• By contrast, FGF17b and FGF18 mimic FGF8a by causing expansion of the midbrain and upregulating midbrain gene expression [5].
• In calvarial bone development of Fgf18-deficient mice generated by gene targeting, the progress of suture closure is delayed [6].
• Here, comparative proteomics and comparative genomics analyses on FGF8, FGF17, and FGF18 orthologs were performed [7].

Anatomical context of Fgf18

• Fgf17 is expressed during gastrulation but at lower levels than Fgf8, while Fgf18 RNA is not expressed until later, in paraxial mesoderm [8].
• In situ hybridization was used to examine the expression of Fgf18 and Fgfr s in adult human articular cartilage [9].
• However, the Fgf18-/- lungs at E18.5 had reduced alveolar space, thicker interstitial mesenchymal compartments, and many embedded capillaries [10].
• Cell proliferation in the Fgf18-/- lungs was also transiently reduced around E17.5, although the expression of marker genes for lung epithelial cells in the Fgf18-/- lungs was not impaired [10].
• FGF-18, a novel member of the fibroblast growth factor family, stimulates hepatic and intestinal proliferation [11].

Regulatory relationships of Fgf18

• Fgf18 is expressed in both osteogenic mesenchymal cells and differentiating osteoblasts during calvarial bone development [6].
• FGF18 represses noggin expression and is induced by calcineurin [12].
• Consistent with this, we showed that the effect of GSK3 inhibition on chondrocyte proliferation is repressed in tissues lacking a receptor for FGF18, FGF receptor 3 [13].

Other interactions of Fgf18

• Fgf17 is expressed later and broader than either Fgf8 or Fgf18 [14].
• Here, we report the expression from early streak stage to midgestation of two newly-identified murine genes, Fgf17 and Fgf18, that are most closely related to Fgf8 (63.7% and 56.8% identical, respectively, at the amino acid level) [8].
• TGF-beta also stimulated expression of FGF18 mRNA in the cultures and the effects of TGF-beta on metatarsal development were blocked or partially blocked by pretreatment with FGF signaling inhibitors [15].
• All these effects of FGF-18 bore a close resemblance to those of FGF-2, whereas FGF-10 affects none of these cells [3].
• This suggests that the regulation of FGF18 expression is a major function of GSK3 during endochondral bone development [13].

Analytical, diagnostic and therapeutic context of Fgf18

• In this study we used a chick electroporation assay and in vitro mouse brain explant experiments to compare the activity of FGF17b and FGF18 to FGF8a and FGF8b [5].
• The two tissues which appeared to be the primary targets of FGF-18 were the liver and small intestine, both of which exhibited histologic evidence of proliferation and showed significant gains in organ weight following 7 (sometimes 3) days of FGF-18 treatment [11].
• This work, thus, identifies FGF18 and FGFR3 as potential molecular targets for intervention in tissue engineering aimed at cartilage repair and regeneration of damaged cartilage [16].
• In further experiments, T(3) enhanced FGF2 and FGF18 activation of the MAPK-signaling pathway but inhibited their activation of signal transducer and activator of transcription-1 [17].
• FGF4 and FGF18 are detected at highest levels by RT-PCR and microarrays [18].

References