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From the Beth Israel Deaconess Medical Center,*
New
England Baptist Bone and Joint Institute, Harvard Institutes of
Medicine, Boston, Massachusetts; the Joslin Diabetes
Center
and the Orthopedic Biomechanics
Laboratory, Beth Israel Deaconess Medical
Center,
Harvard Medical School, Boston,
Massachusetts; the Institute for Biomedical
Engineering,
ETH and University of
Zürich, Zürich, Switzerland; and the Department of
Pathology and Lab Medicine,¶
University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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-
B 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.
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