Canonical Wnt signaling skews TGF-尾 signaling in chondrocytes towards signaling via ALK1 and Smad 1/5/8

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• 作者：Martijn H. van den Bosch ; ¹ ; ^{martijn.vandenbosch@radboudumc.nl" class="auth_mail} ; Arjen B. Blom¹ ; ^{arjen.blom@radboudumc.nl" class="auth_mail} ; Peter L. van Lent ^{peter.vanlent@radboudumc.nl" class="auth_mail} ; Henk M. van Beuningen ^{henk.vanbeuningen@radboudumc.nl" class="auth_mail} ; Esmeralda N. Blaney Davidson ^{esmeralda.blaneydavidson@radboudumc.nl" class="auth_mail} ; Peter M. van der Kraan ^{peter.vanderkraan@radboudumc.nl" class="auth_mail} ; Wim B. van den Berg ^{wim.vandenberg@radboudumc.nl" class="auth_mail}
• 关键词：Osteoarthritis ; Wnt signaling ; TGF-尾 ; Smad signaling ; Chondrocyte hypertrophy
• 刊名：Cellular Signalling
• 出版年：May, 2014
• 年：2014
• 卷：26
• 期：5
• 页码：951-958
• 全文大小：748 K

文摘

Background

Both Wnt signaling and TGF-尾 signaling have been implicated in the regulation of the phenotype of many cell types including chondrocytes, the only cell type present in the articular cartilage. A changed chondrocyte phenotype, resulting in chondrocyte hypertrophy, is one of the main hallmarks of osteoarthritis. TGF-尾 signaling via activin-like kinase (ALK)5, resulting in Smad 2/3 phosphorylation, inhibits chondrocyte hypertrophy. In contrast, TGF-尾 signaling via ALK1, leading to Smad 1/5/8 phosphorylation, has been shown to induce chondrocyte hypertrophy. In this study, we investigated the capability of Wnt3a and WISP1, a protein downstream in canonical Wnt signaling, to skew TGF-尾 signaling in chondrocytes from the protective Smad 2/3 towards the Smad 1/5/8 pathway.

Results

Stimulation with Wnt3a, either alone or in combination with its downstream protein WISP1, decreased TGF-尾-induced C-terminal phosphorylation of Smad 2/3. In addition, both Wnt3a and WISP1 increased Smad 1/5/8 phosphorylation at the C-terminal domain in both murine and human chondrocytes. DKK-1, a selective inhibitor of canonical Wnt signaling, abolished these effects. TGF-尾 signaling via Smad 2/3, measured by the functional CAGA₁₂-Luc reporter construct activity, was decreased by stimulation with Wnt3a in accordance with the decrease in Smad 2/3 phosphorylation found on Western blot. Furthermore, in vivo overexpression of the canonical Wnt8a decreased Smad 2/3 phosphorylation and increased Smad 1/5/8 phosphorylation.

Conclusions

Our data show that canonical Wnt signaling is able to skew TGF-尾 signaling towards dominant signaling via the ALK1/Smad 1/5/8 pathway, which reportedly leads to chondrocyte hypertrophy. In this way canonical Wnts and WISP1, which we found to be increased during experimental osteoarthritis, may contribute to osteoarthritis pathology.