The identification that OPG knockout mice develop osteoporosis and severe arterial calcification [39], along with the observation that RANKL expression increases in calcified arterial tissue [40], and evidence that RANKL induces VSMC calcification in vitro, with OPG preventing this process [41,42], suggests that the RANK/RANKL/OPG/LGR4 axis may serve as a crucial autocrine/paracrine system involved in both bone loss and vascular calcification. The gene discussed is TNFSF11; the disease is calcification.