Identification of NIBAN2-regulated RUNX2 alternative splicing presents novel strategies antagonizing osteoporosis

Abstract

Abstract 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 was found to be tightly associated with bone formation and osteoporosis. Indeed, NIBAN2 promoted osteoblast differentiation, and conditional Niban2 knockout in osteoblasts caused bone loss and insufficient mineralization in mice. Mechanistically, NIBAN2 interacted with the Hnrnpu-cored spliceosome complex and altered its components to regulate the alternative splicing of Runx2, which ultimately caused an increase in full-length Runx2 but a decrease in exon 6-exclusive Runx2 isoforms to reinforce osteoblast differentiation. Most importantly, NIBAN2 was associated with RUNX2 alternative splicing and correlated with bone loss in osteoporosis patients. Niban2 rescued bone loss in ovariectomy-induced osteoporosis in mice. Thus, our research identifies NIBAN2-regulated RUNX2 alternative splicing as a novel mechanism of osteoblast differentiation that may present new strategies for antagonizing osteoporosis.