A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 318; no. 1; pp. 132 - 141
• Main Authors: Medicherla, Satyanarayana, Ma, Jing Ying, Mangadu, Ruban, Jiang, Yebin, Zhao, Jenny J, Almirez, Ramona, Kerr, Irene, Stebbins, Elizabeth G, O'Young, Gilbert, Kapoun, Ann M, Luedtke, Gregory, Chakravarty, Sarvajit, Dugar, Sundeep, Genant, Harry K, Protter, Andrew A
• Format: Journal Article
• Language: English
• Published: United States 01.07.2006
• Subjects: Animals; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Arthritis, Experimental - drug therapy; Arthritis, Experimental - enzymology; Arthritis, Experimental - pathology; Cartilage Diseases - drug therapy; Cartilage Diseases - enzymology; Cartilage Diseases - pathology; Foot Bones - drug effects; Foot Bones - enzymology; Foot Bones - pathology; Male; Mice; Mice, Inbred DBA; Osteoclasts - drug effects; Osteoclasts - enzymology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.098020

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 alpha, interleukin (IL)-1beta, and cyclooxygenase-2, as well as the process of osteoclast differentiation. Therefore, we evaluated whether a p38alpha 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-1beta, 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, p38alpha MAPK inhibition not only attenuates disease progression but also reverses cartilage and bone destruction in mice with advanced CIA disease.