Inhibition of T cell–dependent and RANKL-dependent osteoclastogenic processes associated with high levels of bone mass in interleukin-15 receptor–deficient mice
Article first published online: 29 OCT 2010
Copyright © 2010 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 62, Issue 11, pages 3300–3310, November 2010
How to Cite
Djaafar, S., Pierroz, D. D., Chicheportiche, R., Zheng, X. X., Ferrari, S. L. and Ferrari-Lacraz, S. (2010), Inhibition of T cell–dependent and RANKL-dependent osteoclastogenic processes associated with high levels of bone mass in interleukin-15 receptor–deficient mice. Arthritis & Rheumatism, 62: 3300–3310. doi: 10.1002/art.27645
- Issue published online: 29 OCT 2010
- Article first published online: 29 OCT 2010
- Manuscript Accepted: 29 JUN 2010
- Manuscript Received: 25 MAY 2009
- Swiss National Science Foundation. Grant Numbers: 310000-108453, PMPDA-110347, 631-62937
- Hans Wilsdorf Foundation
- Swiss Foundation for Ageing Research (AETAS)
- Crohn's and Colitis Foundation of America
T cell production of RANKL, interferon-γ (IFNγ), and other cytokines in inflammatory processes such as rheumatoid arthritis or secondary to conditions such as estrogen deficiency stimulates osteoclast activity, which leads to bone resorption and bone loss. The purpose of this study was to characterize the effects of interleukin-15 (IL-15), a master T cell growth factor whose role in bone remodeling remains unknown.
We used mice lacking the IL-15 receptor (IL-15Rα−/−) to investigate the effects of IL-15 on osteoclast development, T cell and dendritic cell activation in vitro and in vivo, bone mass, and microarchitecture in intact and ovariectomized (OVX) mice.
In wild-type (WT) animals, IL-15 and RANKL provided a costimulatory signal for osteoclast development. Spleens from IL-15Rα−/− mice contained few c-Kit+ osteoclast precursors, and the expression of NF-ATc1 and the osteoclastogenic response to RANKL were impaired. In addition, dendritic cell–dependent and T cell–dependent mechanisms of osteoclast activation, including RANKL and IFNγ production, were impaired in IL-15Rα−/− mice. In turn, IL-15Rα−/− T cells failed to stimulate WT osteoclasts, whereas WT T cells failed to stimulate IL-15Rα−/− osteoclasts. Compared with WT mice, both intact and OVX IL-15Rα−/− mice had significantly greater bone mineral density and microarchitecture, including a higher trabecular bone volume fraction and cortical thickness. The numbers of osteoclasts on the bone surface as well as markers of bone turnover were significantly decreased in IL-15Rα−/− mice.
In the absence of IL-15 signaling, several converging mechanisms of osteoclastogenesis are inhibited, both directly and indirectly, through T cells, which leads to a high bone mass phenotype. Targeting the IL-15 pathway may represent a novel therapeutic approach to treating primary and secondary osteoporosis.