Deubiquitinase USP17 Regulates Osteoblast Differentiation by Increasing Osterix Protein Stability

Abstract

Deubiquitinases (DUBs) are essential for bone remodeling by regulating the differentiation of osteoblast and osteoclast. USP17 encodes for a deubiquitinating enzyme, specifically known as ubiquitin-specific protease 17, which plays a critical role in regulating protein stability and cellular signaling pathways. However, the role of USP17 during osteoblast differentiation has not been elusive. In this study, we initially investigated whether USP17 could regulate the differentiation of osteoblasts. Moreover, USP17 overexpression experiments were conducted to assess the impact on osteoblast differentiation induced by bone morphogenetic protein 4 (BMP4). The positive effect was confirmed through alkaline phosphatase (ALP) expression and activity studies since ALP is a representative marker of osteoblast differentiation. To confirm this effect, Usp17 knockdown was performed, and its impact on BMP4-induced osteoblast differentiation was examined. As expected, knockdown of Usp17 led to the suppression of both ALP expression and activity. Mechanistically, it was observed that USP17 interacted with Osterix (Osx), which is a key transcription factor involved in osteoblast differentiation. Furthermore, overexpression of USP17 led to an increase in Osx protein levels. Thus, to investigate whether this effect was due to the intrinsic function of USP17 in deubiquitination, protein stabilization experiments and ubiquitination analysis were conducted. An increase in Osx protein levels was attributed to an enhancement in protein stabilization via USP17-mediated deubiquitination. In conclusion, USP17 participates in the deubiquitination of Osx, contributing to its protein stabilization, and ultimately promoting the differentiation of osteoblasts.

Effects of circulating inflammatory proteins on spinal degenerative diseases: Evidence from genetic correlations and Mendelian randomization study

“…DUBs play an important role in bone remodeling by regulating osteoblasts and osteoclasts, and STAMBP/AMSH is an important subtype in JAMMs. 55 Studies showed that STAMBP can increase NACHT, LRR and PYD domains‐containing protein 7 (NALP7) inflammasome and IL‐1β levels to promote inflammation through deubiquitination. 56 On the other hand, we discovered that STAMBP could raise the risk of spondylolisthesis/spondylolysis.…”

Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis

“…Similarly, members of the Casitas B-lineage lymphoma family, Cbl-b and c-Cbl, have been identified as regulators that diminish the protein stability of Osx during BMP2-induced osteoblast differentiation through ubiquitin–proteasome-mediated degradation 342 . More recently, ubiquitin-specific protease 17 (USP17) has been found to increase Osx protein levels via modulating deubiquitylation, positively impacting osteoblast differentiation as evidenced by enhanced alkaline phosphatase (ALP) expression and activity 343 . These findings open a novel avenue for direct intervention and manipulation of Osx stability, providing a potential approach to enhance or inhibit osteoblast differentiation.…”