Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin.
Autoimmune associated bone disease and intestinal inflammation are closely linked with deregulation and hyperactivation of autoreactive CD4 T cells. How these T cells are activated and mediate disease is not clear. Here we show that in the Interleukin 2-deficient mouse model of autoimmunity spontaneous osteopenia and colitis are caused by increased production of the ligand for receptor activator of NFkappaB (RANKL). RANKL acting via its receptor, receptor activator of NFkappaB (RANK), increases bone turnover and promotes intestinal dendritic cell (DC) survival in vivo. Modulation of RANKL-RANK interactions with exogenous recombinant osteoprotegerin (Fc-OPG) reverses skeletal abnormalities and reduces colitis by decreasing colonic DC numbers. This study identifies a common causal link between bone disease and intestinal inflammation and establishes the importance of DC in mediating colonic inflammation in vivo.
Ashcroft
A J
AJ
Academic Unit of Haematology and Oncology, School of Medicine, University of Leeds, Leeds, United Kingdom.
Cruickshank
S M
SM
Croucher
P I
PI
Perry
M J
MJ
Rollinson
S
S
Lippitt
J M
JM
Child
J A
JA
Dunstan
C
C
Felsburg
P J
PJ
Morgan
G J
GJ
Carding
S R
SR
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D001842:Bone and Bones / Q000187:drug effects* / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006023:Glycoproteins / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D002352:Carrier Proteins; D006023:Glycoproteins; D018398:Homeodomain Proteins; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; C064658:RAG-1 protein