GRK5 Inhibition Attenuates Cartilage Degradation via Decreased NF-κB Signaling
| Autor: | Ichiro Kurakazu, Hidetoshi Tsushima, Mitsumasa Hayashida, Takuya Sueishi, Taisuke Uchida, Norio Goto, Hirofumi Bekki, Masakazu Toya, Martin Lotz, Masanari Kuwahara, Yukio Akasaki, Yasuharu Nakashima |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult Cartilage Articular G-Protein-Coupled Receptor Kinase 5 Male medicine.medical_specialty Adolescent Knee Joint Immunology Aminopyridines 03 medical and health sciences Mice Young Adult 0302 clinical medicine Chondrocytes Rheumatology NF-KappaB Inhibitor alpha In vivo Internal medicine medicine Immunology and Allergy Animals Humans Enzyme Inhibitors Phosphorylation RNA Small Interfering Receptor Aged Regulation of gene expression Aged 80 and over Mice Knockout Chemistry Kinase Cartilage NF-kappa B Middle Aged Osteoarthritis Knee IκBα 030104 developmental biology Endocrinology medicine.anatomical_structure ADAMTS4 Gene Expression Regulation Amlexanox 030220 oncology & carcinogenesis Female medicine.drug Signal Transduction |
| Zdroj: | Arthritisrheumatology (Hoboken, N.J.)References. 72(4) |
| ISSN: | 2326-5205 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text