Blockade of parathyroid hormone-related protein prevents joint destruction and granuloma formation in streptococcal cell wall-induced arthritis

Objective. To determine whether parathyroid hormone-related protein (PTHrP), an interleukin-1β-inducible, bone-resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA. Methods. PTHrP expression and the effect of PTHrP 1-34 neutralizing antibody on disease progression were tested in streptococcal cell wall (SCW)-induced arthritis, an animal model of RA. Results. As has been reported in RA, while serum levels of PTHrP did not change during SCW-induced arthritis, PTHrP expression dramatically increased in the arthritic synovium. Treatment with PTHrP neutralizing antibody (versus control antibody) did not affect joint swelling in SCW-treated animals. However, PTHrP antibody significantly inhibited SCW-induced joint destruction, as measured by its ability to block increases in serum pyridinoline (a marker of cartilage and bone destruction), erosion of articular cartilage, decreases in femoral bone mineral density, and increases in the numbers of osteoclasts in eroded bone. Unexpectedly, granuloma formation at sites of SCW deposition in the liver and spleen was also inhibited by PTHrP antibody, an effect associated with significant decreases in the tissue influx of PTH/PTHrP receptor-positive neutrophils and in SCW-induced neutrophilia. In vitro, neutrophil chemotaxis was stimulated by PTHrP 1-34. Conclusion. These findings suggest that PTHrP, consistent with its previously described osteolytic effects in metastatic bone disease, can also be an important mediator of joint destruction in inflammatory bone disorders, such as RA. Moreover, this study reveals heretofore unknown effects of PTHrP peptides on neutrophil function that could have important implications in the pathogenesis of inflammatory granulomatous disorders.