Abstract
Bisphosphonates (BPs) are the most used bone-specific anti-resorptive agents, often chosen as first-line therapy in several bone diseases characterized by an imbalance between osteoblast-mediated bone production and osteoclast-mediated bone resorption. BPs target the farnesyl pyrophosphate synthase (FPPS) in osteoclasts, reducing bone resorption. Lately, there has been an increasing interest in BPs direct pro-survival/pro-mineralizing properties in osteoblasts and their pain-relieving effects. Even so, molecular targets involved in these effects appear now largely elusive. Ion channels are emerging players in bone homeostasis. Nevertheless, the effects of BPs on these proteins have been poorly described. Here we reviewed the actions of BPs on ion channels in musculoskeletal cells. In particular, the TRPV1 channel is essential for osteoblastogenesis. Since it is involved in bone pain sensation, TRPV1 is a possible alternative target of BPs. Ion channels are emerging targets and anti-target for bisphosphonates. Zoledronic acid can be the first selective musculoskeletal and vascular KATP channel blocker targeting with high affinity the inward rectifier channels Kir6.1-SUR2B and Kir6.2-SUR2A. The action of this drug against the overactive mutants of KCNJ9-ABCC9 genes observed in the Cantu’ Syndrome (CS) may improve the appropriate prescription in those CS patients affected by musculoskeletal disorders such as bone fracture and bone frailty.
Highlights
Bisphosphonates (BPs) are the most used bone-specific anti-resorptive agents
We have recently demonstrated that zoledronic acid is an agonist of TRPV1 ion channel in bone cells, being able to activate strong outward capsazepine-sensitive currents on preosteoblast like cells MC3T3-E1 and native murine/rat mesenchymal stem cells
We found a significant correlation between the combined atrial fibrillation and arrhythmias reactions and the IC50 to block either the Kir6.2-SUR2A and Kir6.1SUR2B channels mimicking the cardiac and vascular KATP channels, respectively
Summary
Bisphosphonates (BPs) are the most used bone-specific anti-resorptive agents. With the Food and drug administration (FDA) approval of alendronate more than 3 decades ago, BPs were introduced in clinical practice (Kennel and Drake, 2009). These data suggest that BPs positively affect bone formation, even in the face of reduced overall bone remodeling These positive effects on osteoblast survival are exerted via different mechanisms apart from inhibiting the mevalonate pathway and producing toxic metabolites inside the osteoclasts. MC3T3-E1 cells and native murine bone marrow-derived osteoblasts undergo mineralization in the presence of capsaicin and sub-micromolar concentration of zoledronic acid (5 × 10−8–10−7 M) These effects were antagonized by capsazepine supporting the role of TRPV1 in this process. CS patients report a large variety of bone malformations, some CS patients may suffer from bone frailty For this purpose, we are investigating the action of zoledronic acid on KATP channel currents of skeletal muscle fibers and bone cells from CS mice to evaluate the potential use of this drug in CS
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
