The research group led by Prof. Long Zhang from Life Sciences Institute (LSI), Zhejiang University has recently published a paper entitled “Ubiquitin-Specific Protease 4 Antagonize Osteoblast Differentiation through Dishevelled” in Journal of Bone and Mineral Research on April 29, 2016. 

The canonical Wnt/β-catenin signaling pathway plays a pivotal role and is essentially required for the osteoblast differentiation and bone formation. Here in this study, we found Ubiquitin Specific Peptidase 4 (USP4) to strongly inhibit the Wnt/β-catenin signaling by removing Lysine-63 linked poly-ubiquitin chain from Dishevelled (Dvl). Ectopic expression of USP4 promoted β-catenin poly-ubiquitination thus inhibited Wnt-induced accumulation of cytosolic β-catenin and counteracted Wnt-induced transcriptional activity. Moreover, USP4 knock-down or USP4 knock-out led to an increase in the active β-catenin levels and in activation of Wnt/β-catenin-induced transcription. Functional studies in C2C12 myoblasts and KS483 osteoprogenitor cells showed that ectopic expression of USP4 resulted in impaired activation of endogenous Wnt3a-induced genes and decreased osteoblast differentiation and mineralization, whereas USP4 depletion showed the opposite effect. These results identify USP4 as a novel regulator of Dvl in Wnt/β-catenin signal and show its involvement in Wnt3a induced osteoblast differentiation.

Ubiquitin-Specific Protease 4 regulates Wnt3a induced mineralization in hMSCs.

Text link: http://onlinelibrary.wiley.com/doi/10.1002/jbmr.2863/abstract