GRK5 Inhibition Attenuates Cartilage Degradation via Decreased NF-κB Signaling

被引:25
作者
Sueishi, Takuya [1 ]
Akasaki, Yukio [1 ]
Goto, Norio [1 ]
Kurakazu, Ichiro [1 ]
Toya, Masakazu [1 ]
Kuwahara, Masanari [1 ]
Uchida, Taisuke [1 ]
Hayashida, Mitsumasa [1 ]
Tsushima, Hidetoshi [1 ]
Bekki, Hirofumi [1 ,2 ]
Lotz, Martin K. [2 ]
Nakashima, Yasuharu [1 ]
机构
[1] Kyushu Univ, Grad Sch Med Sci, Fukuoka, Japan
[2] Scripps Res Inst, San Diego, CA USA
基金
日本学术振兴会;
关键词
COUPLED-RECEPTOR KINASE-5; IN-VIVO; OSTEOARTHRITIS; INFLAMMATION; AMLEXANOX; DELIVERY; IDENTIFICATION; ACCUMULATION; SUPPRESSION; ACTIVATION;
D O I
10.1002/art.41152
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective NF-kappa B-dependent signaling is an important modulator in osteoarthritis (OA), and G protein-coupled receptor kinase 5 (GRK5) regulates the NF-kappa B 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-kappa B 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-kappa B transcriptional activation. On Western blot analysis, GRK5 deletion reduced I kappa B alpha 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-kappa B signaling, and is a potential target for OA treatment. Furthermore, amlexanox may be a major compound in relevant drugs.
引用
收藏
页码:620 / 631
页数:12
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