Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.
Bone remodelling and bone loss are controlled by a balance between the tumour necrosis factor family molecule osteoprotegerin ligand (OPGL) and its decoy receptor osteoprotegerin (OPG). In addition, OPGL regulates lymph node organogenesis, lymphocyte development and interactions between T cells and dendritic cells in the immune system. The OPGL receptor, RANK, is expressed on chondrocytes, osteoclast precursors and mature osteoclasts. OPGL expression in T cells is induced by antigen receptor engagement, which suggests that activated T cells may influence bone metabolism through OPGL and RANK. Here we report that activated T cells can directly trigger osteoclastogenesis through OPGL. Systemic activation of T cells in vivo leads to an OPGL-mediated increase in osteoclastogenesis and bone loss. In a T-cell-dependent model of rat adjuvant arthritis characterized by severe joint inflammation, bone and cartilage destruction and crippling, blocking of OPGL through osteoprotegerin treatment at the onset of disease prevents bone and cartilage destruction but not inflammation. These results show that both systemic and local T-cell activation can lead to OPGL production and subsequent bone loss, and they provide a novel paradigm for T cells as regulators of bone physiology.
Kong
Y Y
YY
Amgen Institute, Toronto, Ontario, Canada.
Feige
U
U
Sarosi
I
I
Bolon
B
B
Tafuri
A
A
Morony
S
S
Capparelli
C
C
Li
J
J
Elliott
R
R
McCabe
S
S
Wong
T
T
Campagnuolo
G
G
Moran
E
E
Bogoch
E R
ER
Van
G
G
Nguyen
L T
LT
Ohashi
P S
PS
Lacey
D L
DL
Fish
E
E
Boyle
W J
WJ
Penninger
J M
JM
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001862:Bone Resorption; D001842:Bone and Bones / Q000473:pathology; D002352:Carrier Proteins / Q000502:physiology*; D002356:Cartilage / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053244:Osteoprotegerin; D053245:RANK Ligand; D051381:Rats; D011917:Rats, Inbred Lew; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D013601:T-Lymphocytes / Q000502:physiology*
D002352:Carrier Proteins; D006023:Glycoproteins; 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; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C506032:Tnfrsf11b protein, rat; C505689:Tnfsf11 protein, mouse