Identification of NIBAN2‐Regulated RUNX2 Alternative Splicing Presents Novel Strategies for Antagonizing Osteoporosis

Osteoporosis is characterized by excessive bone resorption and/or defects in bone formation. Identification of factors promoting osteoblast differentiation may provide potential targets for osteoporosis therapy. Through integral analyses of multiple datasets, NIBAN2 is found to be tightly associated with bone formation and osteoporosis. Indeed, NIBAN2 promotes osteoblast differentiation, and conditional Niban2 knockout in osteoblasts caused bone loss and insufficient mineralization. Mechanistically, NIBAN2 interacts with the HNRNPU-cored spliceosome complex and alters its components to regulate the alternative splicing of RUNX2, which ultimately cause an increase in functional RUNX2 (nuclear localization sequence complete) but a decrease in dysfunctional RUNX2 (exon 6 exclusive) to reinforce osteoblast differentiation. Most importantly, NIBAN2 expression level negatively correlates with RUNX2 spliced isoforms and bone loss in osteoporosis patients. NIBAN2 overexpression rescues bone loss in ovariectomized mice. Thus, this research identifies NIBAN2-regulated RUNX2 alternative splicing as a potential mechanism of osteoblast differentiation that may present strategies for antagonizing osteoporosis.