An RNA G-quadruplex within the sclerostin 3' untranslated region enhances sclerostin expression by blocking miR-4648 binding.

Sclerostin (SOST) serves as a pivotal negative regulator of bone formation, and its dysregulated expression is implicated in the pathogenesis of skeletal disorders, including osteoporosis. While substantial progress has been made in elucidating the intracellular signaling pathways activated by SOST, the molecular mechanisms governing its expression remain less well understood. In this study, we identify an RNA G-quadruplex (RG4) secondary structure within the 3' untranslated region (3' UTR) of SOST. Utilizing biophysical and fluorescent probe analyses, we demonstrate that the SOST RG4 can form a typical parallel RG4 folding topology structure. Functional analyses reveal that the SOST RG4 acts as a crucial positive regulator of cellular SOST expression. Mechanistically, we show that the RG4 structure interferes with the binding of miR-4648 to the SOST 3' UTR, thereby enhancing SOST expression. Furthermore, this regulatory function is potentiated by the RG4-stabilizing ligand, Pyridostatin. Collectively, our findings highlight the biological significance of the RG4 structure in regulating SOST expression and suggest novel strategies for the post-transcriptional modulation of this essential gene in bone biology.