Calcium calmodulin kinase II activity is required for cartilage homeostasis in osteoarthritis.
Calcium calmodulin kinase II activity is required for cartilage homeostasis in osteoarthritis.
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DOI：
10.1038/s41598-021-82067-w
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发表时间：
2021-03-11
影响因子：
4.6
通讯作者：
Dell'Accio F
中科院分区：
文献类型：
--
作者：
Nalesso G;Thorup AS;Eldridge SE;De Palma A;Kaur A;Peddireddi K;Blighe K;Rana S;Stott B;Vincent TL;Thomas BL;Bertrand J;Sherwood J;Fioravanti A;Pitzalis C;Dell'Accio F
WNT配体可以激活发育和再生过程中至关重要的几个信号级联。它们的失调与不同疾病的发生有关。在这里，我们研究了WNT/钙钙调蛋白激酶II（CaMKII）通路在骨关节炎中的作用。我们通过微阵列分析确定了血红素加氧酶I（HMOX 1）和Sox-9作为关节软骨细胞中WNT/CaMKII信号传导的特异性标志物。我们发现，在人类和小鼠骨关节炎中，激活形式的CaMKII，磷酸化CaMKII的表达增加，HMOX 1的表达相应减少，表明疾病进展期间该途径的激活。为了阐明其功能，我们给小鼠施用CaMKII抑制剂KN 93，其中骨关节炎是通过切除内侧半月板前角和膝关节内侧副韧带诱导的。药理学阻断CaMKII加剧了软骨损伤和骨重建。最后，我们发现，在关节软骨细胞中的CaMKII抑制上调表达的基质重塑酶单独和与白细胞介素1的组合。这些结果表明，WNT/CaMKII信号在骨关节炎中具有重要的稳态作用，未来可用于治疗目的。
WNT ligands can activate several signalling cascades of pivotal importance during development and regenerative processes. Their de-regulation has been associated with the onset of different diseases. Here we investigated the role of the WNT/Calcium Calmodulin Kinase II (CaMKII) pathway in osteoarthritis. We identified Heme Oxygenase I (HMOX1) and Sox-9 as specific markers of the WNT/CaMKII signalling in articular chondrocytes through a microarray analysis. We showed that the expression of the activated form of CaMKII, phospho-CaMKII, was increased in human and murine osteoarthritis and the expression of HMOX1 was accordingly reduced, demonstrating the activation of the pathway during disease progression. To elucidate its function, we administered the CaMKII inhibitor KN93 to mice in which osteoarthritis was induced by resection of the anterior horn of the medial meniscus and of the medial collateral ligament in the knee joint. Pharmacological blockade of CaMKII exacerbated cartilage damage and bone remodelling. Finally, we showed that CaMKII inhibition in articular chondrocytes upregulated the expression of matrix remodelling enzymes alone and in combination with Interleukin 1. These results suggest an important homeostatic role of the WNT/CaMKII signalling in osteoarthritis which could be exploited in the future for therapeutic purposes.
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影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
4.6
作者：
Forootan SS;Mutter FE;Kipar A;Iwawaki T;Francis B;Goldring CE;Park BK;Copple IM
通讯作者：
Copple IM
影响因子：
4.6
作者：
Li, Yuwei;Ahrens, Molly J.;Dudley, Andrew T.
通讯作者：
Dudley, Andrew T.
影响因子：
4
作者：
An, Qin-de;Li, Yun-yun;Zhang, Yin-gang
通讯作者：
Zhang, Yin-gang
影响因子：
7
作者：
Botter, S. M.;Glasson, S. S.;van Osch, G. J. V. M.
通讯作者：
van Osch, G. J. V. M.