Thus, this strong interplay between H+ and Ca2+ may occurs also in normal bone cells in the sarcoma microenvironment: it is already well known that TRPVs mediate Ca2+ signalling and are produced in mature osteoclast differentiation to sustain the intracellular Ca2+ level for the maintenance of active NFATc1 that regulates terminal cell differentiation [121], and the presence of an excess of protons in the sarcoma TME may interfere with Ca2+ signalling mediated by TRPVs in osteoclasts and may directly alter the osteoclast physiology and activity. The gene discussed is NFATC1; the disease is sarcoma.