Fenoldopam Sensitizes Primary Cilia-Mediated Mechanosensing to Promote Osteogenic Intercellular Signaling and Whole Bone Adaptation

Bone cells actively respond to mechanical stimuli to direct bone formation, yet there is no current treatment strategy for conditions of low bone mass and osteoporosis designed to target the inherent mechanosensitivity of bone. Our group has previously identified the primary cilium as a critical mechanosensor within bone, and that pharmacologically targeting the primary cilium with fenoldopam can enhance osteocyte mechanosensitivity. Here, we demonstrate that potentiating osteocyte mechanosensing with fenoldopam in vitro promotes pro-osteogenic paracrine signaling to osteoblasts. Conversely, impairing primary cilia formation and the function of key ciliary mechanotransduction proteins attenuates this intercellular signaling cascade. We then utilize an in vivo model of load-induced bone formation to demonstrate that fenoldopam treatment sensitizes bones of both healthy and osteoporotic mice to mechanical stimulation. Furthermore, we show minimal adverse effects of this treatment and demonstrate that prolonged treatment biases trabecular bone adaptation. This work is the first to examine the efficacy of targeting primary cilia-mediated mechanosensing to enhance bone formation in osteoporotic animals. (c) 2022 American Society for Bone and Mineral Research (ASBMR).

Automated summary

This study demonstrates the effectiveness of pharmacologically targeting the primary cilium to enhance bone formation. By potentiating osteocyte mechanosensing, the paracrine signaling to osteoblasts is promoted. Additionally, impairing primary cilia formation weakens this intercellular signaling cascade. In an in vivo model, fenoldopam treatment sensitizes bones to mechanical stimulation and has minimal adverse effects.