Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/ß-catenin signaling.

Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21-/-) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21-/- and Ctsk-cre; Trim21f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/ß-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

Prognostic Bone Metastasis-Associated Immune-Related Genes Regulated by Transcription Factors in Mesothelioma.

Mesothelioma (MESO) is a mesothelial originate neoplasm with high morbidity and mortality. Despite advancement in technology, early diagnosis still lacks effectivity and is full of pitfalls. Approaches of cancer diagnosis and therapy utilizing immune biomarkers and transcription factors (TFs) have attracted more and more attention. But the molecular mechanism of these features in MESO bone metastasis has not been thoroughly studied. Utilizing high-throughput genome sequencing data and lists of specific gene subsets, we performed several data mining algorithm. Single-sample Gene Set Enrichment Analysis (ssGSEA) was applied to identify downstream immune cells. Potential pathways involved in MESO bone metastasis were identified using Gene Oncology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and Cox regression analysis. Ultimately, a model to help early diagnosis and to predict prognosis was constructed based on differentially expressed immune-related genes between bone metastatic and nonmetastatic MESO groups. In conclusion, immune-related gene SDC2, regulated by TFs TCF7L1 and POLR3D, had an important role on immune cell function and infiltration, providing novel biomarkers and therapeutic targets for metastatic MESO.