title: Pulsed low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis.
abstract: 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 (TcREG) by osteoclasts. Here, we show that pulses of low-dose RANKL are needed to induce TcREG, as continuous infusion of identical doses of RANKL by pump did not induce TcREG. We also show that low-dose RANKL can induce TcREGat 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 TcREGinduction 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.
authors: Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Anna
authors: A
authors: Cline-Smith
authors: Division of Bone and Mineral Diseases, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors: Jesse
authors: J
authors: Gibbs
authors: Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Elena
authors: E
authors: Shashkova
authors: Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Zachary S
authors: ZS
authors: Buchwald
authors: Division of Bone and Mineral Diseases, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors: Deborah V
authors: DV
authors: Novack
authors: Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Rajeev
authors: R
authors: Aurora