PubMed日本語 - 線維芽細胞活性化タンパク質とdipeptidylpeptidase 4の抑制は、関節リウマチ滑膜線維芽細胞によって軟骨浸潤を増加させる。―QLifePro医療翻訳医療翻訳 QLifePro


Inhibition of fibroblast activation protein and dipeptidylpeptidase 4 increases cartilage invasion by rheumatoid arthritis synovial fibroblasts.

線維芽細胞活性化タンパク質とdipeptidylpeptidase 4の抑制は、関節リウマチ滑膜線維芽細胞によって軟骨浸潤を増加させる。

Published date


Caroline Ospelt, Joachim C Mertens, Astrid Jüngel, Fabia Brentano, Hanna Maciejewska-Rodriguez, Lars C Huber, Hossein Hemmatazad, Thomas Wüest, Alexander Knuth, Renate E Gay, Beat A Michel, Steffen Gay, Christoph Renner, Stefan Bauer


University Hospital, Zurich, Switzerland.


OBJECTIVE: Since fibroblasts in the synovium of patients with rheumatoid arthritis (RA) express the serine proteases fibroblast activation protein (FAP) and dipeptidylpeptidase 4 (DPP-4)/CD26, we undertook the current study to determine the functional role of both enzymes in the invasion of RA synovial fibroblasts (RASFs) into articular cartilage.


METHODS: Expression of FAP and DPP-4/CD26 by RASFs was analyzed using fluorescence-activated cell sorting and immunocytochemistry. Serine protease activity was measured by cleavage of fluorogenic substrates and inhibited upon treatment with L-glutamyl L-boroproline. The induction and expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in RASFs were detected using real-time polymerase chain reaction. Densitometric measurements of MMPs using immunoblotting confirmed our findings on the messenger RNA level. Stromal cell-derived factor 1 (SDF-1 [CXCL12]), MMP-1, and MMP-3 protein levels were measured using enzyme-linked immunosorbent assay. The impact of FAP and DPP-4/CD26 inhibition on the invasiveness of RASFs was analyzed in the SCID mouse coimplantation model of RA using immunohistochemistry.


RESULTS: Inhibition of serine protease activity of FAP and DPP-4/CD26 in vitro led to increased levels of SDF-1 in concert with MMP-1 and MMP-3, which are downstream effectors of SDF-1 signaling. Using the SCID mouse coimplantation model, inhibition of enzymatic activity in vivo significantly promoted invasion of xenotransplanted RASFs into cotransplanted human cartilage. Zones of cartilage resorption were infiltrated by FAP-expressing RASFs and marked by a significantly higher accumulation of MMP-1 and MMP-3, when compared with controls.


CONCLUSION: Our results indicate a central role for the serine protease activity of FAP and DPP-4/CD26 in protecting articular cartilage against invasion by synovial fibroblasts in RA.


目的関節リウマチ(RA)患者の関節滑膜の線維芽細胞がセリンプロテアーゼ線維芽細胞活性化タンパク質(FAP)とdipeptidylpeptidase 4(DPP-4)/CD26を表すので、我々は関節軟骨にRA滑膜線維芽細胞(RASFs)の浸潤で両方の酵素の機能的な役割を決定するために本研究を行った。

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