Inhibition of Gsk3β in cartilage induces osteoarthritic features through activation of the canonical Wnt signaling pathway

• Published in: Osteoarthritis and cartilage Vol. 19; no. 11; pp. 1363 - 1372
• Main Authors: Miclea, R.L, Siebelt, M, Finos, L, Goeman, J.J, Löwik, C.W.G.M, Oostdijk, W, Weinans, H, Wit, J.M, Robanus-Maandag, E.C, Karperien, M
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2011
• Subjects: Animals; beta Catenin - metabolism; Biomarkers - metabolism; Cartilage degradation; Cartilage, Articular - metabolism; Chondrocyte; Chondrocytes - metabolism; Extracellular Matrix - metabolism; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - physiology; Glycogen Synthase Kinase 3 beta; Glycosaminoglycans - metabolism; Gsk3β; Hindlimb; Metalloproteinase; Mice; Peptide Hydrolases - metabolism; Protein Array Analysis; Rats; Rheumatology; Wnt; Wnt Signaling Pathway - drug effects; Gsk3β; Metalloproteinase; Chondrocyte; Wnt; Cartilage degradation
• ISSN: 1063-4584; 1522-9653
• DOI: 10.1016/j.joca.2011.07.014

Summary Objective In the past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. In this pathway, glycogen synthase kinase-3β (GSK3β) down-regulates transduction of the canonical Wnt signal by promoting degradation of β-catenin. In this study we wanted to further investigate the role of Gsk3β in cartilage maintenance. Design Therefore, we have treated chondrocytes ex vivo and in vivo with GIN, a selective GSK3β 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 β-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 β-catenin, Gsk3β preserves the chondrocytic phenotype, and is involved in maintenance of the cartilage extracellular matrix. Short term β-catenin up-regulation in cartilage secondary to Gsk3β inhibition may be sufficient to induce osteoarthritis-like features in vivo.