Inhibition of Gsk3 beta in cartilage induces osteoarthritic features through activation of the canonical Wnt signaling pathway

RL Miclea, Michiel Siebelt, L Finos, JJ Goeman, Clemens Löwik, W (Wilma) Oostdijk, HH Weinans, JM Wit, EC Robanus-Maandag, M Karperien

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Abstract

Objective: In the past years, the canonical Wnt/beta-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. In this pathway, glycogen synthase kinase-3 beta (GSK3 beta) down-regulates transduction of the canonical Wnt signal by promoting degradation of beta-catenin. In this study we wanted to further investigate the role of Gsk3 beta in cartilage maintenance. Design: Therefore, we have treated chondrocytes ex vivo and in vivo with GIN, a selective GSK3 beta inhibitor. Results: In E17.5 fetal mouse metatarsals, GIN treatment resulted in loss of expression of cartilage markers and decreased chondrocyte proliferation from day 1 onward. Late (3 days) effects of GIN included cartilage matrix degradation and increased apoptosis. Prolonged (7 days) GIN treatment resulted in resorption of the metatarsal. These changes were confirmed by microarray analysis showing a decrease in expression of typical chondrocyte markers and induction of expression of proteinases involved in cartilage matrix degradation. An intra-articular injection of GIN in rat knee joints induced nuclear accumulation of beta-catenin in chondrocytes 72 h later. Three intra-articular GIN injections with a 2 days interval were associated with surface fibrillation, a decrease in glycosaminoglycan expression and chondrocyte hypocellularity 6 weeks later. Conclusions: These results suggest that, by down-regulating beta-catenin, Gsk3 beta preserves the chondrocytic phenotype, and is involved in maintenance of the cartilage extracellular matrix. Short term beta-catenin up-regulation in cartilage secondary to Gsk3 beta inhibition may be sufficient to induce osteoarthritis-like features in vivo. (C) 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Original languageUndefined/Unknown
Pages (from-to)1363-1372
Number of pages10
JournalOsteoarthritis and Cartilage
Volume19
Issue number11
DOIs
Publication statusPublished - 2011

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