Mechanisms of TNF-α– and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis
Christopher T. Ritchlin, … , David G. Hicks, Edward M. Schwarz
Christopher T. Ritchlin, … , David G. Hicks, Edward M. Schwarz
Published March 15, 2003
Citation Information: J Clin Invest. 2003;111(6):821-831. https://doi.org/10.1172/JCI16069.
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Categories: Article Bone biology

Mechanisms of TNF-α– and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis

Abstract

Psoriatic arthritis (PsA) is an inflammatory joint disease characterized by extensive bone resorption. The mechanisms underlying this matrix loss have not been elucidated. We report here that blood samples from PsA patients, particularly those with bone erosions visible on plain radiographs, exhibit a marked increase in osteoclast precursors (OCPs) compared with those from healthy controls. Moreover, PsA PBMCs readily formed osteoclasts in vitro without exogenous receptor activator of NF-κB ligand (RANKL) or MCSF. Both osteoprotegerin (OPG) and anti-TNF antibodies inhibited osteoclast formation. Additionally, cultured PsA PBMCs spontaneously secreted higher levels of TNF-α than did healthy controls. In vivo, OCP frequency declined substantially in PsA patients following treatment with anti-TNF agents. Immunohistochemical analysis of subchondral bone and synovium revealed RANK-positive perivascular mononuclear cells and osteoclasts in PsA specimens. RANKL expression was dramatically upregulated in the synovial lining layer, while OPG immunostaining was restricted to the endothelium. These results suggest a model for understanding the pathogenesis of aggressive bone erosions in PsA. OCPs arise from TNF-α–activated PBMCs that migrate to the inflamed synovium and subchondral bone, where they are exposed to unopposed RANKL and TNF-α. This leads to osteoclastogenesis at the erosion front and in subchondral bone, resulting in a bidirectional assault on psoriatic bone.

Authors

Christopher T. Ritchlin, Sally A. Haas-Smith, Ping Li, David G. Hicks, Edward M. Schwarz

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Figure 6

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RANK expression in the psoriatic joint. Tissues from PsA patients contai...
RANK expression in the psoriatic joint. Tissues from PsA patients containing synovium and bone were obtained following surgery and processed for immunohistochemistry as described in Methods. Antibodies specific for RANK stain red-brown. RANK-positive osteoclasts (arrows) are prominently located at the synovial edge of the pannus-bone interface, shown photographed at ×20 (a), and RANK-positive mononuclear cells increase in number moving from the endothelium (asterisks) to the erosion front (×20) (b). In subchondral bone, RANK-positive osteoclasts were observed in cutting cones that are void of other cell types, as shown photographed at ×20 magnification (c). RANK-positive mononuclear cells and osteoclasts (arrows) surround an endothelial cell traversing subchondral bone (d).