Showing Latest Articles
Fibroblast growth factor receptor 1 is principally responsible for fibroblast growth factor 2-induced catabolic activities in human articular chondrocytes Full Text
Arthritis Research & Therapy, 08/22/2011
Yan D et al. – FGFR1 is the major mediator with the degenerative potential in the presence of FGF-2 in human adult articular chondrocytes. FGFR1 activation by FGF-2 promotes catabolism and impedes anabolism. Disruption of the balance between FGFR1 and FGFR3 signaling ratio may contribute to the pathophysiology of OA.
Methods- Primary human articular chondrocytes were cultured in monolayer (24 hours) or alginate beads (21 days), and stimulated with FGF-2 or FGF18, in the presence or absence of FGFR1 (FGF receptor 1) inhibitor
- Proteoglycan accumulation and chondrocyte proliferation were assessed by dimethylmethylene blue (DMMB) assay and DNA assay, respectively
- Expression of FGFRs (FGFR1~FGFR4) was assessed by flow cytometry, immunoblotting, and quantitative real-time PCR (qPCR)
- Distinctive roles of FGFR1 and FGFR3 after stimulation with FGF-2 were evaluated using either pharmacological inhibitors or FGFR small interfering RNA (siRNA)
- Chondrocyte proliferation was significantly enhanced in the presence of FGF-2 stimulation, which was inhibited by the pharmacological inhibitor of FGFR1
- Proteoglycan accumulation reduced by 50% in presence of FGF-2, and this reduction was successfully rescued by FGFR1 inhibitor
- FGFR1 inhibitors also fully reversed the upregulation of MMP-13 expression and promoter activity stimulated by FGF-2
- Blockade of FGFR1 signaling by either chemical inhibitors or siRNA targeting FGFR1 rather than FGFR3 abrogated the upregulation of matrix metalloproteinases 13 (MMP-13) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif 5 (ADAMTS5), as well as downregulation of aggrecan after FGF-2 stimulation
- Flow cytometry, qPCR and immunoblotting analyses suggested that FGFR1 and FGFR3 were the major FGFR isoforms expressed in human articular chondrocytes
- FGFR1 was activated more potently than FGFR3 upon FGF-2 stimulation
- In osteoarthritic chondrocytes, FGFR3 was significantly down regulated (P<0.05) with a concomitant increase in FGFR1 to FGFR3 expression ratio (P<0.05), compared to normal chondrocytes
- Results demonstrate that FGFR3 was negatively regulated by FGF-2 at transcriptional level through FGFR1-ERK (extracellular signal-regulated kinase) signaling pathway in human articular chondrocytes