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

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 osteoarthr...

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Published inScientific 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
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LanguageEnglish
Published London Nature Publishing Group UK 11.03.2021
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Abstract 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.
AbstractList Abstract 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.
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.
ArticleNumber 5682
Author Vincent, Tonia Louise
Thorup, Anne-Sophie
De Palma, Anna
Sherwood, Joanna
Pitzalis, Costantino
Thomas, Bethan Lynne
Bertrand, Jessica
Rana, Sharmila
Kaur, Amanpreet
Nalesso, Giovanna
Eldridge, Suzanne Elizabeth
Stott, Bryony
Fioravanti, Antonella
Dell’Accio, Francesco
Blighe, Kevin
Peddireddi, Kiran
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  organization: Kennedy Institute of Rheumatology, University of Oxford
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SSID ssj0000529419
Score 2.449708
Snippet WNT ligands can activate several signalling cascades of pivotal importance during development and regenerative processes. Their de-regulation has been...
Abstract WNT ligands can activate several signalling cascades of pivotal importance during development and regenerative processes. Their de-regulation has been...
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pubmedcentral
proquest
crossref
pubmed
springer
SourceType Open Website
Open Access Repository
Aggregation Database
Index Database
Publisher
StartPage 5682
SubjectTerms 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
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Title Calcium calmodulin kinase II activity is required for cartilage homeostasis in osteoarthritis
URI https://link.springer.com/article/10.1038/s41598-021-82067-w
https://www.ncbi.nlm.nih.gov/pubmed/33707504
https://www.proquest.com/docview/2500162653
https://search.proquest.com/docview/2501261546
https://pubmed.ncbi.nlm.nih.gov/PMC7952598
https://doaj.org/article/4f50238f6e9a41a8bd45f631bc8299e2
Volume 11
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