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GRK 5 Inhibition Attenuates Cartilage Degradation via Decreased NF ‐κB Signaling
Author(s) -
Sueishi Takuya,
Akasaki Yukio,
Goto Norio,
Kurakazu Ichiro,
Toya Masakazu,
Kuwahara Masanari,
Uchida Taisuke,
Hayashida Mitsumasa,
Tsushima Hidetoshi,
Bekki Hirofumi,
Lotz Martin K.,
Nakashima Yasuharu
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41152
Subject(s) - western blot , signal transduction , nf κb , receptor , osteoarthritis , phosphorylation , iκbα , chemistry , nfkb1 , microbiology and biotechnology , in vivo , knockout mouse , pathogenesis , cartilage , biology , medicine , pathology , transcription factor , gene , anatomy , biochemistry , alternative medicine
Objective NF ‐κB–dependent signaling is an important modulator in osteoarthritis ( OA ), and G protein–coupled receptor kinase 5 ( GRK 5) regulates the NF ‐κB pathway. This study was undertaken to investigate the functional involvement of GRK 5 in OA pathogenesis. Methods GRK 5 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 GRK 5‐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 GRK 5 inhibitor, every 5 days for 8 weeks. Results GRK 5 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 MMP 13 [ P < 0.01], and 2.66‐fold decrease in ADAMTS 4 [ P < 0.01]). Conversely, GRK 5 overexpression significantly increased the expression of OA ‐related catabolic mediators and NF ‐κB transcriptional activation. On Western blot analysis, GRK 5 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 GRK 5 deletion and intraarticular amlexanox protected mouse cartilage against OA . Conclusion Our results suggest that GRK 5 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.