AUTHOR=Zhang Xiangzheng , Wang Yike , Zheng Miao , Wei Qi , Zhang Ruizhi , Zhu Keyu , Zhai Qiaocheng , Xu Youjia 

TITLE=IMPC-based screening revealed that ROBO1 can regulate osteoporosis by inhibiting osteogenic differentiation

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2024.1450215

DOI=10.3389/fcell.2024.1450215

ISSN=2296-634X

ABSTRACT=<sec><title>Introduction</title><p>The utilization of denosumab in treating osteoporosis highlights promising prospects for osteoporosis intervention guided by gene targets. While omics-based research into osteoporosis pathogenesis yields a plethora of potential gene targets for clinical transformation, identifying effective gene targets has posed challenges.</p></sec><sec><title>Methods</title><p>We first queried the omics data of osteoporosis clinical samples on PubMed, used International Mouse Phenotyping Consortium (IMPC) to screen differentially expressed genes, and conducted preliminary functional verification of candidate genes in human Saos2 cells through osteogenic differentiation and mineralization experiments. We then selected the candidate genes with the most significant effects on osteogenic differentiation and further verified the osteogenic differentiation and mineralization functions in mouse 3T3-E1 and bone marrow mesenchymal stem cells (BMSC). Finally, we used RNA-seq to explore the regulation of osteogenesis by the target gene.</p></sec><sec><title>Results</title><p>We identified <italic>PPP2R2A</italic>, <italic>RRBP1</italic>, <italic>HSPB6</italic>, <italic>SLC22A15</italic>, <italic>ADAMTS4</italic>, <italic>ATP8B1</italic>, <italic>CTNNB1</italic>, <italic>ROBO1</italic>, and <italic>EFR3B</italic>, which may contribute to osteoporosis. <italic>ROBO1</italic> was the most significant regulator of osteogenesis in both human and mouse osteoblast. The inhibitory effect of Robo1 knockdown on osteogenic differentiation may be related to the activation of inflammatory signaling pathways.</p></sec><sec><title>Conclusion</title><p>Our study provides several novel molecular mechanisms involved in the pathogenesis of osteoporosis. <italic>ROBO1</italic> is a potential target for osteoporosis intervention.</p></sec>