Calcium calmodulin kinase II activity is required for cartilage homeostasis in osteoarthritis

• Published in: Scientific reports Vol. 11; no. 1; p. 5682
• Main Authors: Nalesso, Giovanna, Thorup, Anne-Sophie, Eldridge, Suzanne Elizabeth, De Palma, Anna, Kaur, Amanpreet, Peddireddi, Kiran, Blighe, Kevin, Rana, Sharmila, Stott, Bryony, Vincent, Tonia Louise, Thomas, Bethan Lynne, Bertrand, Jessica, Sherwood, Joanna, Fioravanti, Antonella, Pitzalis, Costantino, Dell’Accio, Francesco
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/80/304; 631/80/86; Aged; Animals; Arthritis; Bone Remodeling; Ca2+/calmodulin-dependent protein kinase II; Calcium; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calmodulin; Cartilage; Cartilage diseases; Cartilage, Articular - enzymology; Cartilage, Articular - pathology; Cattle; Chondrocytes; Chondrocytes - metabolism; Chondrocytes - pathology; Disease Models, Animal; Female; Gene Expression Regulation, Enzymologic; Heme; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Interleukin 1; Interleukin-1beta - metabolism; Kinases; Knee; Male; Meniscus; Mice; Mice, Inbred C57BL; Middle Aged; Models, Biological; multidisciplinary; Osteoarthritis; Osteoarthritis - enzymology; Osteoarthritis - genetics; Osteoarthritis - pathology; Oxygenase; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - genetics; Protein Isoforms - metabolism; Science; Science (multidisciplinary); Signal transduction; Therapeutic applications; Transcriptome - genetics; Up-Regulation; Wnt protein; Wnt3 Protein - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-82067-w

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.