TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis.
There is considerable evidence that osteoclasts are involved in the pathogenesis of focal bone erosion in rheumatoid arthritis. Tumor necrosis factor-related activation-induced cytokine, also known as receptor activator of nuclear factor-kappaB ligand (TRANCE/RANKL) is an essential factor for osteoclast differentiation. In addition to its role in osteoclast differentiation and activation, TRANCE/RANKL also functions to augment T-cell dendritic cell cooperative interactions. To further evaluate the role of osteoclasts in focal bone erosion in arthritis, we generated inflammatory arthritis in the TRANCE/RANKL knockout mouse using a serum transfer model that bypasses the requirement for T-cell activation. These animals exhibit an osteopetrotic phenotype characterized by the absence of osteoclasts. Inflammation, measured by clinical signs of arthritis and histopathological scoring, was comparable in wild-type and TRANCE/RANKL knockout mice. Microcomputed tomography and histopathological analysis demonstrated that the degree of bone erosion in TRANCE/RANKL knockout mice was dramatically reduced compared to that seen in control littermate mice. In contrast, cartilage erosion was present in both control littermate and TRANCE/RANKL knockout mice. These results confirm the central role of osteoclasts in the pathogenesis of bone erosion in arthritis and demonstrate distinct mechanisms of cartilage destruction and bone erosion in this animal model of arthritis.
Pettit
A R
AR
Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA.
Ji
H
H
von Stechow
D
D
Müller
R
R
Goldring
S R
SR
Choi
Y
Y
Benoist
C
C
Gravallese
E M
EM
D000818:Animals; D001168:Arthritis / Q000097:blood / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism*; D001803:Blood Transfusion; D001842:Bone and Bones / Q000000981:diagnostic imaging* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002358:Cartilage, Articular / Q000000981:diagnostic imaging / Q000473:pathology; D004195:Disease Models, Animal; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D014057:Tomography, X-Ray Computed
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse