What is the mechanism of bone destruction in psoriatic arthritis?
Psoriatic arthritis (PsA), like rheumatoid arthritis (RA), causes bone erosion and joint destruction. Features that distinguish PsA from RA, however, include inflammation and calcification at tendinous insertions (enthesitis) and extensive resorption of the bone of the distal phalanges (acrolysis). The mechanisms of bone resorption in PsA are poorly understood. However, the presence of adjacent bone resorption and new bone formation suggests a disordered pattern of bone remodeling in the psoriatic joint.
Osteoclasts, the principal cells responsible for bone resorption, are derived from mononuclear cell precursors of the monocyte/macrophage lineage. Pathological bone resorption may be due to an increase in the number of these precursors. In fact, elevated numbers of circulating osteoclast precursors (OCPs) have been identified in the peripheral blood or bone marrow of patients with other disorders of bone, including multiple myeloma and Pagets disease. Ritchlin et al (Journal of Clinical Investigation 111:821-831, 2003) investigated the frequency of OCPs in peripheral blood of patients with PsA and the pro- and anti-osteoclastogenic factors present in the synovium and bone of PsA patients.
Results: In PsA patients, particularly those with bone erosions on joint xrays, a marked increase in the frequency of OCPs was observed in blood compared to healthy controls. Peripheral blood mononuclear cells (PBMCs) from PsA patients readily formed osteoclasts in vitro without exogenous RANKL or MCSF. Addition of osteoprotegerin (OPG) and anti-TNF antibodies inhibited this in vitro osteoclast formation. Cultured PsA PBMCs spontaneously secreted higher levels of TNF-alpha than healthy controls. In vivo, OCP frequency declined significantly in PsA patients following treatment with TNF antagonists. Immunohistochemical analysis of subchondral bone and synovia revealed RANK-positive perivascular mononuclear cells and osteoclasts in PsA specimens. RANKL expression was dramatically upregulated in the synovial lining layer, while OPG (which can counteract the osteoclast promoting activity of RANKL) immunostaining was restricted to the endothelium.
Conclusions: These results suggest that high circulating levels of TNF-alpha induce maturation of PBMCs to osteoclast precursors (OCPs). OCPs migrate and enter PsA synovium or bone via TNF-alpha upregulated endothelial adhesion molecules where they engage RANKL expressing stromal cells and additional TNF-alpha. This induces full maturation to osteoclasts and bone resorption can proceed.
Editorial Comment: As the authors point out, this is the first study demonstrating the presence of increased numbers of circulating OCPs in patients with inflammatory arthritis. Osteoclasts arise from monocyte precursors and must enter the bone compartment from blood. This study provides some clues as to the mechanisms of OCP maturation in the periphery and in the local environment of the joint, and suggest that osteoclastogenesis occurs both at the erosion front (at the pannus-bone junction) and in subchondral bone, resulting in a bi-directional assault on psoriatic bone. The investigators have not convincingly shown, however, that this mechanism is unique to PsA and it is likely that it is a generic response common to most destructive, inflammatory types of arthritis. Similar mechanisms have been demonstrated in the synovium of RA patients, although the frequency of OCPs in the periphery has not been examined in detail. Nonetheless, these are very interesting data and advance our understanding of the initial steps leading to bone destruction in states of inflammatory arthritis.
