Inhibition of T cell-dependent and RANKL-dependent osteoclastogenic processes associated with high levels of bone mass in interleukin-15 receptor-deficient mice

Autor: Sylvie Ferrari-Lacraz, Dominique D. Pierroz, Souad Djaafar, Rachel Chicheportiche, Xin Xiao Zheng, S. Ferrari
Jazyk: angličtina
Rok vydání: 2010
Předmět:
musculoskeletal diseases
medicine.medical_specialty
Bone density
Osteoclasts/*metabolism
T-Lymphocytes
T cell
Immunology
Blotting
Western
Osteoclasts
Receptors
Interleukin-15/genetics/*metabolism
Bone and Bones/*metabolism
Spleen/metabolism
Bone and Bones
Bone resorption
Bone remodeling
T-Lymphocytes/*metabolism
Mice
Rheumatology
Osteoclast
Bone Density
Internal medicine
medicine
Immunology and Allergy
Animals
Pharmacology (medical)
ddc:610
Bone Resorption
Cells
Cultured
ddc:616
Mice
Knockout
biology
Receptors
Interleukin-15
Chemistry
Reverse Transcriptase Polymerase Chain Reaction
RANK Ligand
Cell Differentiation
Dendritic cell
medicine.anatomical_structure
Endocrinology
Interleukin 15
RANKL
ddc:618.97
RANK Ligand/genetics/*metabolism
biology.protein
Female
Bone Resorption/*metabolism
Spleen
Signal Transduction
Zdroj: Arthritis and Rheumatism, Vol. 62, No 11 (2010) pp. 3300-3310
ISSN: 0004-3591
Popis: OBJECTIVE: T cell production of RANKL, interferon-gamma (IFNgamma), 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. METHODS: We used mice lacking the IL-15 receptor (IL-15Ralpha(-/-) ) 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. RESULTS: In wild-type (WT) animals, IL-15 and RANKL provided a costimulatory signal for osteoclast development. Spleens from IL-15Ralpha(-/-) 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 IFNgamma production, were impaired in IL-15Ralpha(-/-) mice. In turn, IL-15Ralpha(-/-) T cells failed to stimulate WT osteoclasts, whereas WT T cells failed to stimulate IL-15Ralpha(-/-) osteoclasts. Compared with WT mice, both intact and OVX IL-15Ralpha(-/-) 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-15Ralpha(-/-) mice. CONCLUSION: 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.
Databáze: OpenAIRE
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