Ubiquitin‐Specific Protease 4 Antagonizes Osteoblast Differentiation Through Dishevelled

• Published in: Journal of bone and mineral research Vol. 31; no. 10; pp. 1888 - 1898
• Main Authors: Zhou, Fangfang, Li, Fang, Fang, Pengfei, Dai, Tong, Yang, Bing, van Dam, Hans, Jia, Junling, Zheng, Min, Zhang, Long
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.10.2016
• Subjects: Cell Differentiation - physiology; DISHEVELLED; Dishevelled Proteins - genetics; Dishevelled Proteins - metabolism; HeLa Cells; Humans; OSTEOBLAST DIFFERENTIATION; Osteoblasts - metabolism; Polyubiquitin - genetics; Polyubiquitin - metabolism; Ubiquitin-Specific Proteases - genetics; Ubiquitin-Specific Proteases - metabolism; UBIQUITINATION; USP4; Wnt Signaling Pathway - physiology; Wnt3a; Wnt3A Protein - genetics; Wnt3A Protein - metabolism; β‐CATENIN; UBIQUITINATION; β-CATENIN; OSTEOBLAST DIFFERENTIATION; USP4; DISHEVELLED; Wnt3a
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.2863

ABSTRACT The canonical Wnt/β‐catenin signaling pathway plays a pivotal role and is essentially required for the osteoblast differentiation and bone formation. 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 and thus inhibited Wnt‐induced accumulation of cytosolic β‐catenin and counteracted Wnt‐induced transcriptional activity. Moreover, USP4 knockdown or USP4 knockout 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. © 2016 American Society for Bone and Mineral Research.