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

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.