Zoledronic Acid Activates TRPV1 Channels: Possible Role in Cell Proliferation and Pain

Bisphosphonates (BPs) are the most used bone specific anti‐resorptive drugs. Lately there is an increasing interest in BPs capability to prolong osteoblasts lifespan and mineralize; however, the mechanism of action which underpin these effects are nowadays poorly understood. In addition, an increasing concern about BPs pain‐relieving effects is now emerging. Empirical evidence showed BPs may exert anti‐nociceptive, anti‐hyperalgesia and anti‐allodynic properties against multiple stimuli; targets involved in these analgesic effects remains elusive. FDA alert showed that the chronic use of BPs is linked with an increased risk of musculoskeletal pain; mechanisms underlying this sensation are not known. TRPV1 channel is actually recognized to play a key role in bone formation process; as well, it appeared to be involved in bone pain sensation. Capsaicin, a selective agonist of TRPV1 channel, is used for treating different bone pain conditions. We have recently demonstrated that the BP Zoledronic acid (ZOL) can activate TRPV1 currents on osteoblasts. In the mineralization assay, the co‐application of ZOL with capsazepine, an antagonist of TRPV1 ion channel, reduced ZOL‐induced mineralization (Scala et al., Cancer 2019). We tested ZOL effects on TRPV1 ion channel in differentiated neuronal SH‐SY5Y cells and in HEK293 cells transfected with cDNA codifying for WT and PI(4,5)P2‐binding site mutant TRPV1 ion channels. In whole‐cell patch clamp experiments on neuronal SH‐SY5Y cells, ZOL (100μM) activated strong outward currents both at negative and positive voltages. At positive membrane voltages ZOL (100μM)‐ evoked currents were closed after the application of capsazepine (1μM). On WT TRPV1 channel expressed on HEK293 cells, ZOL (100 μM) activates currents by 37% at −60 mV, by +81% at +60 mV and +80% at +180 mV (Vm). As well, on K694A mutant, ZOL was able to activate currents by +10%, +63% and +76% at −60 mV, +60 mV and +180 mV (Vm), respectively. On the contrary, no activation of currents was observed on the R579A mutant. The ZOL‐induced activation of TRPV1 channel contributes to the mineralization of osteoblasts and to the pain‐relieving effect of ZOL in neurones. Experiments on mutant TRPV1 ion channel suggest that the arginine in the S4–S5 linker of the channel is essential for the drug interaction. Support or Funding Information This research was funded by Reg. Puglia (Italy) project “Cluster in Bioimaging” code QZYCUM0 D.T and A.S., and Fondecyt grants 1150273, 1190293 R.L.. R.S. was supported by GLOBAL THESIS Study (2016–2017) by Univ. degli Studi di Bari “Aldo Moro” at CINV “Centro Interdisciplinario De Neurociencia De Valparaíso”.