Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects.
Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects.
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DOI：
10.3390/ijms23147933
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发表时间：
2022-07-19
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
g蛋白偶联受体激酶2 （GRK2）是多种疾病中炎症和病理性巨噬细胞表型的重要调节因子。我们假设Gβγ-GRK2信号促进骨关节炎（OA）的早期炎症反应和软骨细胞损失。利用12周龄雄性C57BL/6小鼠内侧半月板（DMM）模型的不稳定性，我们确定了Gβγ-GRK2信号在滑膜炎、巨噬细胞激活和OA发展中的作用。我们从DMM手术前2天开始，每天给予Gβγ抑制剂“gallein”和GRK2抑制剂“paroxetine”，持续1或12周，从而在DMM时实现了Gβγ-GRK2抑制。通过组织形态测量法评估滑膜和软骨的结构变化，并检测分子事件和巨噬细胞活化。我们利用SW982和THP1细胞研究了Gβγ-GRK2在体外滑膜炎和巨噬细胞活化中的直接作用。在DMM时开始的持续Gβγ-GRK2抑制比延迟治疗更有效地减弱OA发展和减少软骨细胞损失。GRK2表达和M1巨噬细胞表型在炎症滑膜中升高，而DMM后1周和12周的早期galgalin和帕罗西汀治疗导致其减少和M2巨噬细胞表型上调。体外实验表明，Gβγ-GRK2抑制可减轻滑膜细胞炎症和M1表型。我们发现早期Gβγ-GRK2抑制比延迟抑制对OA有更高的治疗效果，因为它通过抑制早期炎症反应来阻止OA的发展。
The G-protein-coupled receptor kinase 2 (GRK2) is an important regulator of inflammation and pathological macrophage phenotype in a variety of diseases. We hypothesize that Gβγ-GRK2 signaling promotes the early inflammatory response and chondrocyte loss in osteoarthritis (OA). Using the destabilization of the medial meniscus (DMM) model in 12-week-old male C57BL/6 mice, we determined the role of Gβγ-GRK2 signaling in synovitis, macrophage activation, and OA development. We achieved Gβγ-GRK2 inhibition at the time of DMM by administering the Gβγ inhibitor “gallein” and the GRK2 inhibitor “paroxetine” daily, starting from 2 days before DMM surgery, for a duration of 1 or 12 weeks. Synovial and cartilage structural changes were evaluated by histomorphometry, and molecular events and macrophage activation were examined. We studied the direct role of Gβγ-GRK2 in synovitis and macrophage activation in vitro using SW982 and THP1 cells. Continuous Gβγ-GRK2 inhibition initiated at the time of DMM attenuated OA development and decreased chondrocyte loss more effectively than delayed treatment. GRK2 expression and the M1 macrophage phenotype were elevated in the inflamed synovium, while early gallein and paroxetine treatment for 1 and 12 weeks following DMM resulted in their reduction and an upregulated M2 macrophage phenotype. In vitro experiments showed that Gβγ-GRK2 inhibition attenuated synoviocyte inflammation and the M1 phenotype. We show that early Gβγ-GRK2 inhibition is of higher therapeutic efficacy in OA than delayed inhibition, as it prevents OA development by inhibiting the early inflammatory response.
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影响因子：
27.4
作者：
Atukorala I;Kwoh CK;Guermazi A;Roemer FW;Boudreau RM;Hannon MJ;Hunter DJ
通讯作者：
Hunter DJ
影响因子：
17.1
作者：
Carlson, Elijah L.;Karuppagounder, Vengadeshprabhu;Kamal, Fadia
通讯作者：
Kamal, Fadia
影响因子：
2.7
作者：
Liu, Baolong;Zhang, Maoquan;Yang, Hao
通讯作者：
Yang, Hao
影响因子：
7
作者：
Glasson, S. S.;Blanchet, T. J.;Morris, E. A.
通讯作者：
Morris, E. A.
DOI：
10.1002/art.23006
发表时间：
2007-10-15
期刊：
ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH
影响因子：
--
作者：
Diaz-Torne, C.;Schumacher, H. R.;Pessler, F.
通讯作者：
Pessler, F.