Pulsed low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis

A number of studies in model animal systems and in the clinic have established that RANKL promotes bone resorption. Paradoxically, we found that pulsing ovariectomized mice with low-dose RANKL suppressed bone resorption, decreased the levels of proinflammatory effector T cells and led to increased bone mass. This effect of RANKL is mediated through the induction of FoxP3⁺CD25⁺ regulatory CD8⁺ T cells (Tc_REG) by osteoclasts. Here, we show that pulses of low-dose RANKL are needed to induce Tc_REG, as continuous infusion of identical doses of RANKL by pump did not induce Tc_REG. We also show that low-dose RANKL can induce Tc_REG at 2, 3, 6, and 10 weeks after ovariectomy. Our results show that low-dose RANKL treatment in ovariectomized mice is optimal at once-per-month doses to maintain the bone mass. Finally, we found that treatment of ovariectomized mice with the Cathepsin K inhibitor odanacatib also blocked Tc_REG induction by low-dose RANKL. We interpret this result to indicate that antigens presented to CD8⁺ T cells by osteoclasts are derived from the bone protein matrix because Cathepsin K degrades collagen in the bone. Taken together, our studies provide a basis for using low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis.