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可能通过新型强效透明质酸酶 KIAA1199 的抑制活性，将一种口服抗骨质疏松药物伊普黄酮重新定位用于治疗炎症性关节炎。

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

机构信息

Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan.

Department of Rehabilitation Medicine, Nagoya University Hospital, 65 Tsurumai, Showa, Nagoya 466-8550, Japan.

出版信息

Int J Mol Sci. 2022 Apr 7;23(8):4089. doi: 10.3390/ijms23084089.

DOI:10.3390/ijms23084089
PMID:35456905
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9030858/
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 ( = 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.

摘要

KIAA1199 在炎症性关节炎中具有很强的透明质酸酶活性。本研究旨在寻找一种能够降低 KIAA1199 活性的药物，并阐明其对炎症性关节炎的影响。大鼠软骨肉瘤（RCS）细胞用阿利新蓝（AB）强烈染色。在过表达 KIAA1199 基因的 RCS 细胞（RCS-KIAA）中，其染色能力降低。我们筛选了能够恢复 RCS-KIAA 中 AB 染色能力的药物。通过粒子排除试验、HA ELISA、RT-PCR 和 Western blot 评估药物的作用。我们进一步评估了 HA 积累以及纤维母细胞样滑膜细胞（FLS）中 MMP1 和 MMP3 的表达。在体内，评估了药物对胶原诱导性关节炎小鼠症状和血清 HA 浓度的影响。白藜芦醇被鉴定为能够恢复 AB 染色性，其浓度为 23%。细胞外基质形成呈剂量依赖性显著增加（=0.006）。白藜芦醇增加了 TNF-α刺激的 FLS 中 HA 的积累，并抑制了 MMP1 和 MMP3 的表达。在体内，白藜芦醇显著改善了症状并降低了血清 HA 浓度。结论：我们鉴定出白藜芦醇，它对 KIAA1199 活性具有抑制作用。白藜芦醇可能是一种有前途的治疗药物，因为它能够降低炎症性关节炎中的 KIAA1199 活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/acc0711b396b/ijms-23-04089-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/0088d8bfa9f0/ijms-23-04089-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/dbbbb53eb451/ijms-23-04089-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/466bff224d6d/ijms-23-04089-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/86a2c26a736c/ijms-23-04089-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/acc0711b396b/ijms-23-04089-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/0088d8bfa9f0/ijms-23-04089-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/dbbbb53eb451/ijms-23-04089-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/466bff224d6d/ijms-23-04089-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/86a2c26a736c/ijms-23-04089-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ace/9030858/acc0711b396b/ijms-23-04089-g005.jpg

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