Abstract
The attenuated degradation of articular cartilage by cartilage-specific deletion of fibroblast growth factor receptor 1 (FGFR1) in adult mice suggests that FGFR1 is a potential target for treating osteoarthritis (OA). The goal of the current study was to investigate the effect of a novel non-ATP-competitive FGFR1 inhibitor, G141, on the catabolic events in human articular chondrocytes and cartilage explants and on the progression of cartilage degradation in a murine model of OA. G141 was screened and identified via cell-free kinase-inhibition assay. In the in vitro study, G141 decreased the mRNA levels of catabolic markers ADAMTS-5 and MMP-13, the phosphorylation of Erk1/2, JNK and p38 MAPK, and the protein level of MMP-13 in human articular chondrocytes. In the ex vivo study, proteoglycan loss was markedly reduced in G141 treated human cartilage explants. For the in vivo study, intra-articular injection of G141 attenuated the surgical destabilization of the medial meniscus (DMM) induced cartilage destruction and chondrocyte hypertrophy and apoptosis in mice. Our data suggest that pharmacologically antagonize FGFR1 using G141 protects articular cartilage from osteoarthritic changes, and intra-articular injection of G141 is potentially an effective therapy to alleviate OA progression.
Highlights
That FGFR1 is a potential therapy target for treating OA and pharmacological FGFR1 antagonists may prevent cartilage degradation and/or improve cartilage homeostasis
Our observations suggest that G141 reduces the catabolic events in fibroblast growth factors (FGFs)-2 or IL-1β treated human articular chondrocytes and human cartilage explants, and intra-articular injection of G141 protects articular cartilage from degradation after destabilization of the medial meniscus (DMM) in mice
To test the specificity of G141, we further measured the inhibitory effect of G141 on other receptor tyrosine kinases (RTKs), including VEGFR2, PDGFRβ, FGFR2 and FGFR3
Summary
That FGFR1 is a potential therapy target for treating OA and pharmacological FGFR1 antagonists may prevent cartilage degradation and/or improve cartilage homeostasis. Several small molecules, such as PD173074, SU5402 and PD166866, have been used as FGFR tyrosine kinase inhibitors[10]. These inhibitors were designed based on their competitive inhibition of the ATP-binding domain of FGFR1. We analyzed the impact of a novel non-ATP-competitive FGFR1 inhibitor, G141, on FGF-2 or IL-1β –induced catabolic events in human articular chondrocytes and cartilage explants. Our observations suggest that G141 reduces the catabolic events in FGF-2 or IL-1β treated human articular chondrocytes and human cartilage explants, and intra-articular injection of G141 protects articular cartilage from degradation after DMM in mice
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