Abstract
The ubiquitin protease pathway plays important role in human bone marrow-derived mesenchymal stem cell (hBMSC) differentiation, including osteogenesis. However, the function of deubiquitinating enzymes in osteogenic differentiation of hBMSCs remains poorly understood. In this study, we aimed to investigate the role of ubiquitin-specific protease 53 (USP53) in the osteogenic differentiation of hBMSCs. Based on re-analysis of the Gene Expression Omnibus database, USP53 was selected as a positive regulator of osteogenic differentiation in hBMSCs. Overexpression of USP53 by lentivirus enhanced osteogenesis in hBMSCs, whereas knockdown of USP53 by lentivirus inhibited osteogenesis in hBMSCs. In addition, USP53 overexpression increased the level of active β-catenin and enhanced the osteogenic differentiation of hBMSCs. This effect was reversed by the Wnt/β-catenin inhibitor DKK1. Mass spectrometry showed that USP53 interacted with F-box only protein 31 (FBXO31) to promote proteasomal degradation of β-catenin. Inhibition of the osteogenic differentiation of hBMSCs by FBXO31 was partially rescued by USP53 overexpression. Animal studies showed that hBMSCs with USP53 overexpression significantly promoted bone regeneration in mice with calvarial defects. These results suggested that USP53 may be a target for gene therapy for bone regeneration.
Highlights
Bone homeostasis is regulated by the balance of osteogenesis and osteoclastogenesis[1,2,3]
Expression of upregulated Deubiquitinating enzymes (DUBs) during the osteogenic differentiation of human bone marrow-derived mesenchymal stem cell (hBMSC) and selection of ubiquitinspecific protease 53 (USP53) as a DUB-associated molecule Based on Gene Expression Omnibus (GEO) datasets and previous studies[24], commonly upregulated DUBs in hBMSC osteogenesis were analyzed (Supplementary Table S1)
Resulting in reduced osteogenesis of hBMSCs. This phenomenon was rescued after modulating the expression of USP53 (Fig. 5j). These results demonstrated that the F-box only protein 31 (FBXO31)-mediated reduction of osteogenesis in hBMSCs was significantly blocked in the presence of USP53
Summary
Bone homeostasis is regulated by the balance of osteogenesis (bone formation) and osteoclastogenesis (bone resorption)[1,2,3]. The imbalance of these processes leads to low bone density and deterioration of the bone matrix, which increases the risk of skeletal disorders, such as osteoporosis[4]. Several therapeutics have been developed to maintain bone homeostasis[7,8], including bone-forming and antiresorptive compounds. These compounds have serious side effects, including peptic ulcers, The ubiquitin-proteasome pathway (UPP) is an ATP-. Deubiquitinating enzymes (DUBs) remove ubiquitin chains from a target protein, controlling the function and stability of the protein[12,13]
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