Date: Monday, October 22, 2018
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Fibroblast growth factor receptor3 (FGFR3) is a member of the family of 4 different receptors (FGFR1-4) with more than 23 identified ligands FGF1-23. Each FGFR has different isoforms resulting from natural alternative splice variants and hence can bind more than one FGF ligands. Upon binding FGF ligands, fibroblast growth factor receptors (FGFRs) trigger various intracellular signaling pathways to regulate important biological processes.
Methods: Differential expression profiling of dermal cells from SSc patients and healthy volunteers were performed employing GEArray cDNA microarray, qPCR, Western Blot, immunohistochemistry and immunofluorescence analyses. Selective inhibitors in conjunction with knockdown and knockout strategies were used to target FGF9/FGFR3 signaling in vitro and in vivo. FGFR3/FGF9 target genes were identified by Affymetrix gene arrays. The anti-fibrotic potential of FGF9/FGFR3 inactivation was evaluated in two mouse models of SSc: skin fibrosis induced by bleomycin and tight skin-1 (TSK) mice.
Results: FGFR3, specifically the isoform FGFR3 IIIb, expression was significantly upregulated in the dermis and dermal fibroblasts of SSc patients as compared to healthy volunteers. In contrast, the expression of other members of the FGFR family (FGFR1,2 and 4)was not induced in SSc. FGFR3 IIIb binds only FGF1 and FGF9 and we found significant increase in the levels of FGF9, in contrast to FGF1, in SSc patients as compared to healthy people.
To screen for FGFR3 regulated genes in fibroblasts, which might contribute to the pathogenesis of SSc, FGFR3Act mice with constitutive FGFR3 signaling and FGFR3KO mice, lacking FGFR3, were differentially screened by Affymetrix gene chips. We found that FGFR3Act mice express significantly elevated levels of the profibrotic mediators monocyte chemoattractant protein-1(MCP-1), connective tissue growth factor(CTGF), interleukin-4 receptor α(IL4Rα), endothelin-1(ET-1) and its receptor endothelin-receptor B (EDNRB). Further analyses revealed that FGF9/FGFR3 stimulates the expression of these profibrotic mediators via ERK- and p38-dependent pathways.
Genetic knockout of FGFR3 ameliorates skin fibrosis in TSK mice and in bleomycin-induced fibrosis. TSK or bleomycin-challenged mice displayed reduced dermal thickening, decreased myofibroblast counts and lower hydroxyproline content upon inactivation of FGFR3. Confirming the translational potential of these findings, we demonstrate pharmacological inactivation of FGFR3 by PD173074 could induce the regression of experimental fibrosis in bleomycin-challenged or in TSK mice.
Conclusion: We have identified and characterized FGFR3 signaling as a novel mediator of fibroblast activation and tissue fibrosis in SSc. FGFR3, regulates a network of major profibrotic mediators including CTGF, MCP-1, ET-1 and its receptor EDNRB and IL4Rα. Thus targeting of this major upstream regulator would deactivate several profibrotic pathways simultaneously.We could demonstrate successfully that the targeted inhibition of FGFR3 ameliorated fibrosis in different preclinical models of SSc. Our findings may have direct translational implications as FGFR3 inhibitors are currently in development.
To cite this abstract in AMA style:Chakraborty D, Summa L, Trinh-Minh T, Chen CW, Soare A, Ramming A, Distler O, Schett G, Distler J. FGFR3/ FGF9 Regulates the Activity of Profibrotic Cytokine and Growth Factor Pathways to Drive Fibroblast Activation and Tissue Fibrosis in Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/fgfr3-fgf9-regulates-the-activity-of-profibrotic-cytokine-and-growth-factor-pathways-to-drive-fibroblast-activation-and-tissue-fibrosis-in-systemic-sclerosis/. Accessed September 24, 2021.
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