Hyaluronan Oligosaccharides Induce MMP-1 and-3 via Transcriptional Activation of NF-kappa B and p38 MAPK in Rheumatoid Synovial Fibroblasts

作者：Hanabayashi Masahiro; Takahashi Nobunori^*; Sobue Yasumori; Hirabara Shinya; Ishiguro Naoki; Kojima Toshihisa

来源：PLos One, 2016, 11(8): e0161875.

DOI：10.1371/journal.pone.0161875

Objective
To explore the effect of hyaluronan oligosaccharides (HAoligos) on interactions between HA and its principal receptor, CD44, in rheumatoid synovial fibroblasts (RSFs) and matrix metalloproteinase (MMP) production.
Methods
RSFs were isolated from rheumatoid synovial tissue. HA distribution was visualized by immunocytochemistry. MMP-1 and MMP-3 induction was analyzed by real-time RT-PCR and immunoblotting. The interaction between HAoligos and their MMP-producing receptors was tested by blocking with anti-CD44 and anti-Toll-like receptor 4 (TLR-4). Phosphorylation of nuclear factor kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK) was analyzed by immunoblotting.
Results
Endogenous HA decreased after treatment with HAoligos, while MMP-1 and MMP-3 expression increased in a dose-dependent manner. Pretreatment with anti-CD44 or anti-TLR-4 antibody significantly reduced the effect of HAoligos on MMP-1 and MMP-3 mRNA expression. NF-kappa B and p38 MAPK phosphorylation was enhanced by HAoligos pretreated with anti-TLR-4, and HAoligo-induced MMP production was blocked with an inhibitor of NF-kappa B and p38 MAPK pathways.
Conclusions
Disruptive changes in CD44-HA interactions by HAoligos enhanced MMP-1 and MMP-3 production via activation of NF-kappa B and p38 MAPK signaling pathways in RSFs.

• 出版日期2016-8-26