Possible Repositioning of an Oral Anti-Osteoporotic Drug, Ipriflavone, for Treatment of Inflammatory Arthritis via Inhibitory Activity of KIAA1199, a Novel Potent Hyaluronidase

Abstract

KIAA1199 has a strong hyaluronidase activity in inflammatory arthritis. This study aimed to identify a drug that could reduce KIAA1199 activity and clarify its effects on inflammatory arthritis. Rat chondrosarcoma (RCS) cells were strongly stained with Alcian blue (AB). Its stainability was reduced in RCS cells, which were over-expressed with the KIAA1199 gene (RCS-KIAA). We screened the drugs that restore the AB stainability in RCS-KIAA. The effects of the drug were evaluated by particle exclusion assay, HA ELISA, RT-PCR, and Western blotting. We further evaluated the HA accumulation and the MMP1 and three expressions in fibroblast-like synoviocytes (FLS). In vivo, the effects of the drug on symptoms and serum concentration of HA in a collagen-induced arthritis mouse were evaluated. Ipriflavone was identified to restore AB stainability at 23%. Extracellular matrix formation was significantly increased in a dose-dependent manner (p = 0.006). Ipriflavone increased the HA accumulation and suppressed the MMP1 and MMP3 expression on TNF-α stimulated FLS. In vivo, Ipriflavone significantly improved the symptoms and reduced the serum concentrations of HA. Conclusions: We identified Ipriflavone, which has inhibitory effects on KIAA1199 activity. Ipriflavone may be a therapeutic candidate based on its reduction of KIAA1199 activity in inflammatory arthritis.

Development of Therapeutic Agent for Osteoarthritis via Inhibition of KIAA1199 Activity: Effect of Ipriflavone In Vivo

“…In a previous study, ipriflavone showed the ability to suppress KIAA1199 activity and inhibited HA depolymerization in fibroblast-like synoviocytes (FLSs) stimulated with TNFα, whereas in the present study, ipriflavone reduced the protein expression of KIAA1199 in the OA cartilage [19]. The mechanism by which ipriflavone directly suppresses KIAA1199 protein expression is unknown.…”

“…The results of this study revealed that ipriflavone, which was shown to inhibit KIAA1199 [19], could inhibit cartilage degradation in a mouse OA model with DMM surgery. In addition, the inhibitory effects of ipriflavone were confirmed by the results of the bovine cartilage explant culture under IL-1β stimulation.…”

“…Ipriflavone recovered the pericellular matrix formation of KIAA1199-overexpressed RCS cells. In a collageninduced arthritis model, ipriflavone significantly improved the symptoms and reduced serum HA concentrations, suggesting the effectiveness of ipriflavone for arthritis, such as rheumatoid arthritis [19]. However, the effects of ipriflavone on OA, which is the most common degenerative disease of the joint, have not been examined yet.…”

Research on the biological mechanism and potential application of CEMIP

“…Therefore, CEMIP may have a positive correlation with MMP2, MMP7, MMP13, and MMP14 and regulate tumor cell EMT through MMPs to promote tumor cell migration. Koike et al (9) reported that ipriflavone can be a drug that inhibits the hyaluronidase activity of CEMIP and inhibits the expression of MMP1 and MMP3 in FLS cells stimulated by TNF-a.…”

“…Abnormal expression of CEMIP can also regulate non-neoplastic diseases, such as inflammation and infection. Studies have shown that the anti-CEMIP monoclonal antibody (anti-CEMIP), ipriflavone, and paclitaxel (PTX) combined with the latest nanosphere-targeted drug delivery technology can make CEMIP as a therapeutic target to inhibit inflammation or tumor development (9,10).…”