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

Abstract

Objective. To determine whether parathyroid hormone-related protein (PTHrP), an interleukin-1␤-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.

Comparative Effects of Two Gingerol-Containing Zingiber officinale Extracts on Experimental Rheumatoid Arthritis

“…19,20,23 Granuloma formation in liver was assessed in hematoxylin and eosin (H&E) stained sections of liver using standard criteria 19,22–24. An index of articular cartilage destruction in day 28 hind joint distal tibias was determined, as previously described, using hematoxylin and eosin (H&E) stained sections (0 = normal; 1 = minimal destruction, 2 = at least 50% destroyed, 3 = entirely destroyed) 20,22…”

“…The in vivo model used, streptococcal cell wall (SCW)-induced arthritis, is a well-characterized animal model of RA 22–24. In this model, over a 28 day course, female Lewis rats develop an initial acute phase of joint swelling followed by a chronic phase of inflammation that is associated with actual joint destruction.…”

Turmeric Extracts Containing Curcuminoids Prevent Experimental Rheumatoid Arthritis

“…[18][19][20] Where indicated, inhibitory effects of treatments on AI were calculated on day 3 for the acute phase or day 28 for the chronic phase of joint swelling. To monitor for possible toxic effects of treatments in normal or SCW-treated animals, daily weights were recorded, and serum creatinine and alamine aminotransferase (ALT) levels in blood samples obtained 28 days after injection of SCW (or vehicle) were determined using a Hemagen Diagnostics Endocheck Plus Chemistry analyzer to monitor for possible renal-or hepato-toxicity, respectively.…”

“…21,22 In addition, a granulomatous inflammatory response, similar to that responsible for inactivating tuberculosis bacilli by walling off the invading bacteria, occurs in the liver and spleen of these animals at sites of SCW deposition. [18][19][20] …”

Evolutionary medicine and bone loss in chronic inflammatory diseases—A theory of inflammation-related osteopenia

“…In addition, inflamed tissue and activated immune cells can produce parathyroid hormone-related peptide (PTHrP), which can be elevated in acute and chronic inflammation (64–66). Endotoxin can directly induce PTHrP secretion (67), and blockade of PTHrP reduces bone loss in experimental arthritis (68). Thus, both PTH and PTHrP, do not protect bone in acute and chronic inflammation, which most probably depends on the circumstances of high inflammation and appearance of other bone-resorbing factors.…”