Loss of intraflagellar transport 140 in osteoblasts cripples bone fracture healing

The indispensability of primary cilia in skeletal development has been widely recognized. We have previously shown that intraflagellar transport 140 (IFT140), a protein component of a bidirectional intraflagellar transport system required for ciliary function, controls bone development and dentinogenesis. However, it remains unknown whether IFT140 functionally contributes to bone fracture rehabilitation. Here an osteotomy-induced femoral fracture model was generated in Ift140-transgenic (Ift140-TG) and osteoblast-specific Ift140-conditional knockout (Ift140-cKO) mice. Micro-computed tomography, osteogenic induction, qualitative polymerase chain reaction, and toluidine blue and safranin O/fast green staining assays were used to characterize the dynamics of bone fracture healing from various perspectives. We found that IFT140 was relatively enriched in the bone callus and decreased in fracture-susceptible aged, or diabetic bones. Ift140-cKO mice had impaired osteogenic differentiation from bone mesenchymal stem cells, lower bone mass, and delayed fracture closure, whereas Ift140-TG mice had promising healing outcomes. Overall, our findings demonstrated for the first time that IFT140 has a beneficial role in fracture repair. Future investigation of the primary cilium in the context of aging and osteoporosis would certainly benefit patients at high risk of bone fractures.