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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A Selective p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

Scios Inc., Fremont, California (S.M., J.Y.M., R.M., R.A., I.K., E.G.S., G.O.Y., A.M.K., G.L., S.C., S.D., A.A.P.); and Osteoporosis and Arthritis Research Group, University of California, San Francisco, California (Y.J., J.J.Z., H.K.G.)

Destruction of cartilage and bone is a poorly managed hallmark of human rheumatoid arthritis (RA). p38 Mitogen-activated protein kinase (MAPK) has been shown to regulate key proinflammatory pathways in RA, including tumor necrosis factor , interleukin (IL)-1, and cyclooxygenase-2, as well as the process of osteoclast differentiation. Therefore, we evaluated whether a p38 MAPK inhibitor, indole-5-carboxamide (SD-282), could modulate cartilage and bone destruction in a mouse model of RA induced with bovine type II collagen [collagen-induced arthritis (CIA)]. In mice with early disease, SD-282 treatment significantly improved clinical severity scores, reduced bone and cartilage loss, and reduced mRNA levels of proinflammatory genes in paw tissue, including IL-1, IL-6, and cyclooxygenase-2. Notably, SD-282 treatment of mice with advanced disease resulted in significant improvement in clinical severity scoring and paw swelling, a reversal in bone and cartilage destruction as assessed by histology, bone volume fraction and thickness, and three-dimensional image analysis. These changes were accompanied by reduced osteoclast number and lowered levels of serum cartilage oligomeric matrix protein, a marker of cartilage breakdown. Thus, in a model of experimental arthritis associated with significant osteolysis, p38 MAPK inhibition not only attenuates disease progression but also reverses cartilage and bone destruction in mice with advanced CIA disease.

Address correspondence to: Satyanarayana Medicherla, Scios Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555. E-mail: smediche{at}scius.jnj.com

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