Ubiquitin modification in osteogenic differentiation and bone formation: From mechanisms to clinical significance

Abstract

The ubiquitin-proteasome system is an important pathway for mediating posttranslational modification and protein homeostasis and exerts a wide range of functions in diverse biological processes, including stem cell differentiation, DNA repair, and cell cycle regulation. Many studies have shown that ubiquitination modification plays a critical role in regulating the osteogenic differentiation of stem cells and bone formation through various mechanisms. This review summarizes current progress on the effects and mechanisms of ubiquitin modification on transcription factors and signaling pathways involved in osteogenic differentiation. Moreover, the review highlights the latest advances in the clinical application of drugs in bone tissue engineering. A thorough understanding of ubiquitin modifications may provide promising therapeutic targets for stem cell-based bone tissue engineering.

Keywords: epigenetics; mesenchymal stem cells; osteogenic differentiation; protein deubiquitinases; ubiquitin modification.

FIGURE 1

Overview of the included articles for the role and mechanism of ubiquitin modification in osteogenic differentiation of stem cells. (A), Flow diagram illustrating the study screening and inclusion process. (B), Statistics for the numbers of publications in different years. (C), Types of enzymes of the included articles. The number refers to the number of relevant literatures. USPs, ubiquitin-specific proteases; UCHs, Ubiquitin C-Terminal Hydrolase; OTUs, ovarian tumor-related proteases; MJDs, Machado-Josephin domain proteases; JAMMs, Jabl/MPN domain associated metalloisopeptidase; E3, ubiquitin ligases.

FIGURE 2

The UPS system mediated signaling pathway and regulatory factors during osteogenic differentiation of mesenchymal stem cells are shown. (A) FGF signaling: Smurfl inhibits JNK signaling by promoting MEKK2 ubiquitination and degradation, and negatively regulates FGF signaling. Cbl can reduce the ubiquitination of PDGFR and FGFR2, thus inhibiting FGF signaling. (B) BMP signaling: USP4 can deubiquitinate TI3RI and Smad4, and enhance BMP signaling. USP9X can antagonize Smad4 monoubiquitination and enhance BMP signaling. USP34 can activate Smad1/5/8 to enhance BMP signaling. UCH-L3 can deubiquitinate and stabilize Smadl, and enhance BMP signaling. OTUB1 deubiquitinates the p-Smad2/3 complex and enhances BMP signaling. Smurfl and Smurf2 induce Smad1/5/8 ubiquitination and negatively regulates BMP signaling. Smurfl and WWP1 promote ubiquitination and degradation of JunB and inhibit BMP signaling. Itch enhances JunB by ubiquitinating ReIA/Re1B and positively regulates BMP signaling. RSP5 induces ubiquitination of PKB/Akt and positively regulates BMP signaling. TRIM21 accelerated the degradation of Akt to enhance BMP signaling. Cbl reduces BMP signaling by inhibiting PI3K-PKB/Akt pathway and ubiquiting BMP2. TRAF4 positively regulates BMP signaling by ubiquitinating Smurf2. (C) Hedgehog signaling: OTUB2 enhances Hh signaling through deubiquitinating Gli2. (D) Wnt signaling: USP4 enhances Wnt signaling through deubiquitinating and stabilizing P-catenin. Conversely, USP4 inhibits Wnt signaling by deubiquitinating Dvl. USP9X enhances Wnt signaling through deubiquitinating Dv12. USP8 enhances Wnt signaling through deubiquitinating FZD5. USP53 inhibits proteasome degradation of p-catenin by interacting with FBXO31 and enhance Wnt signaling. USP7 can activate Wnt signaling through deubiquitinating P-catenin. USP26 can activate Wnt signaling by stabilizing p-catenin. Rnf185 inhibits the Wnt signaling by promoting ubiquitin and degradation of Dv12. CDC20 enhances Wnt signaling by promoting P65 degradation in an APC11-dependent manner. (E) Sonic hedgehog (Shh) signaling: A20 inhibits polyubiquitination of TRAF6. (F) MSX1: USP11 can deubiquitinate the MSX1 protein. (G) RUNX2: USP34 can stabilize RUNX2. WWP2 catalyzes the monoubiquitination of RUNX2. c-Cbl mediates STAT5 ubiquitination and inhibits RUNX2. Skp2 targets Runx2 degradation. TRIM16 stabilizes RUNX2 protein levels. (H) Osteoblast: MYSM1 can affect the maturation and differentiation of osteoblasts. Fbw7 negatively regulates Osx protein stability and osteoblast differentiation.