Abstract

Osteoporosis (OP) is characterized by impaired osteoblast-mediated bone formation and reduced mineralization, which increases fracture risk and challenges global skeletal health. Ddx17 (DEAD-box helicase 17) is implicated in multiple cancers, but its role and mechanism in bone biology, especially in osteoblast differentiation and osteoporosis pathogenesis remain unclear. In this study, we demonstrated that Ddx17 expression was significantly reduced in trabecular bones of patients with osteoporosis. During osteoblastic differentiation of MC3T3-E1 and C3H10T1/2 cells, Ddx17 expression levels increased gradually in a time-dependent manner. Loss-of-function and gain-of-function experiments revealed that Ddx17 promoted osteoblast proliferation and differentiation. Mechanistically, Ddx17 was a direct substrate of Prmt1 (protein arginine methyltransferase 1), which specifically catalyzed ADMA modification of Ddx17 at R426, thereby enhancing Ddx17 protein stability. Stabilized Ddx17 modulated the alternative splicing of Sh2b1 mRNA, thereby promoting the expression of Sh2b1-T1 while suppressing that of Sh2b1-T2. Rescue experiments demonstrated that re-expression of Sh2b1-T1, but not Sh2b1-T2, reversed the impairment of osteoblast differentiation triggered by Ddx17 knockdown. Taken together, these findings underscore the critical role of the Prmt1-Ddx17-Sh2b1 axis in regulating osteoblast differentiation and suggest this axis as a promising therapeutic target for osteoporosis.