BACKGROUND: Intraflagellar transport 80 (IFT80) is vital for primary cilia which can sense and transduce mechanical signals. Mechanical stimuli expedite osteoblastic differentiation and bone formation in mesenchymal stem cells (MSCs). However, how IFT80 regulates mechanical transduction in MSCs remains unclear. BASIC PROCEDURE: To investigate the role of IFT80 in bone development and mechanical transduction, MSC-specific knock-out IFT80 (Prx1 MAIN FINDINGS: In our study, Prx1 PRINCIPAL CONCLUSIONS: IFT80 and TRPA1 cooperatively regulate osteoblastic differentiation and bone formation in response to mechanical stimulation. These findings suggest that IFT80 and TRPA1 are critical for skeletal homeostasis and may serve as potential therapeutic targets for skeletal disorders.