Basic Calcium Phosphate Crystals Induce Osteoarthritis-Associated Changes in Phenotype Markers in Primary Human Chondrocytes by a Calcium/Calmodulin Kinase 2-Dependent Mechanism
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Chondrocytes in osteoarthritis undergo a phenotype shift leading to increased production of cartilage-degrading enzymes. There are similarities between the phenotype of osteoarthritic chondrocytes and those of growth plate chondrocytes. Hydroxyapatite can promote chondrocyte differentiation in the growth plate. Basic calcium phosphate (BCP) crystals (which consist of hydroxyapatite, octacalcium apatite and tricalcium phosphate) are frequently found in osteoarthritic joints. The objective of this study was to determine whether BCP crystals induce disease-associated changes in phenotypic marker expression in chondrocytes. Primary human chondrocytes isolated from macroscopically normal cartilage were treated with BCP for up to 48 h. Expression of indian hedgehog (IHH), matrix metalloproteinase 13 (MMP13), interleukin-6 (IL-6) and type X collagen (COLX) were higher, and expression of sry-box 9 (SOX9) lower, in BCP-treated chondrocytes (50 µg/mL) compared to untreated controls. COLX protein was also present in BCP-treated chondrocytes. Intracellular calcium and levels of phosphorylated and total calcium/calmodulin kinase 2 (CaMK2) were elevated following BCP treatment due to BCP-induced release of calcium from intracellular stores. CaMK2 inhibition or knockdown ameliorated the BCP-induced changes in SOX9, IHH, COLX, IL-6 and MMP13 expression. BCP crystals induce osteoarthritis-associated changes in phenotypic marker expression in chondrocytes by calcium-mediated activation of CaMK2. The presence of BCP crystals in osteoarthritic joints may contribute to disease progression.
KeywordsCrystal arthropathy Chondrocyte hypertrophy Hydroxyapatite
This study was funded by an Arthritis New Zealand project grant (Grant No. R267) and a Sir Charles Hercus Health Research Fellowship, Health Research Council New Zealand (Grant No. 16/022) to RCP.
Support from funders was financial only. Funders were not involved in any aspect of the study, the preparation of the manuscript or the decision to publish.
Compliance with Ethical Standards
Conflict of interest
Jing Rong, Bregina Pool, Mark Zhu, Jacob Munro, Jillian Cornish, Geraldine M. McCarthy, Nicola Dalbeth, Raewyn Poulsen declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
Human tissue used in this study was obtained from patient donors with informed consent and with the approval of the Health and Disability Ethics Committee (New Zealand).
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