GRK5 Inhibition Attenuates Cartilage Degradation via Decreased NF-κB Signaling

Takuya Sueishi, Yukio Akasaki, Norio Goto, Ichiro Kurakazu, Masakazu Toya, Masanari Kuwahara, Taisuke Uchida, Mitsumasa Hayashida, Hidetoshi Tsushima, Hirofumi Bekki, Martin K. Lotz, Yasuharu Nakashima

研究成果: ジャーナルへの寄稿記事

抜粋

Objective: NF-κB–dependent signaling is an important modulator in osteoarthritis (OA), and G protein–coupled receptor kinase 5 (GRK5) regulates the NF-κB pathway. This study was undertaken to investigate the functional involvement of GRK5 in OA pathogenesis. Methods: GRK5 expression in normal and OA human knee joints was analyzed immunohistochemically. Gain- or loss-of-function experiments were performed using human and mouse chondrocytes. OA was induced in GRK5-knockout mice by destabilization of the medial meniscus, and histologic examination was performed. OA was also induced in wild-type mice, which were then treated with an intraarticular injection of amlexanox, a selective GRK5 inhibitor, every 5 days for 8 weeks. Results: GRK5 protein expression was increased in human OA cartilage. In vitro, expression levels of OA-related factors and NF-κB transcriptional activation were down-regulated by suppression of the GRK5 gene in human OA chondrocytes (3.49-fold decrease in IL6 [P < 0.01], 2.43-fold decrease in MMP13 [P < 0.01], and 2.66-fold decrease in ADAMTS4 [P < 0.01]). Conversely, GRK5 overexpression significantly increased the expression of OA-related catabolic mediators and NF-κB transcriptional activation. On Western blot analysis, GRK5 deletion reduced IκBα phosphorylation (up to 4.4-fold decrease [P < 0.05]) and decreased p65 nuclear translocation (up to 6.4-fold decrease [P < 0.01]) in mouse chondrocytes. In vivo, both GRK5 deletion and intraarticular amlexanox protected mouse cartilage against OA. Conclusion: Our results suggest that GRK5 regulates cartilage degradation through a catabolic response mediated by NF-κB signaling, and is a potential target for OA treatment. Furthermore, amlexanox may be a major compound in relevant drugs.

元の言語英語
ページ(範囲)620-631
ページ数12
ジャーナルArthritis and Rheumatology
72
発行部数4
DOI
出版物ステータス出版済み - 4 1 2020

    フィンガープリント

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology

これを引用