A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis
| Autor: | Irene Kerr, Ruban Mangadu, Jing Ying Ma, Ramona Almirez, Gilbert O'Young, Jenny Zhao, Harry K. Genant, Andrew A. Protter, Ann M. Kapoun, Yebin Jiang, Gregory R. Luedtke, Satyanarayana Medicherla, Elizabeth G. Stebbins, Sarvajit Chakravarty, Sundeep Dugar |
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| Rok vydání: | 2006 |
| Předmět: |
Male
medicine.medical_specialty Osteolysis Type II collagen Arthritis Osteoclasts p38 Mitogen-Activated Protein Kinases Proinflammatory cytokine Mice Osteoclast Internal medicine medicine Animals Protein Kinase Inhibitors Pharmacology Cartilage oligomeric matrix protein biology business.industry Cartilage Foot Bones Mitogen-Activated Protein Kinase Inhibitor medicine.disease Arthritis Experimental medicine.anatomical_structure Endocrinology Mice Inbred DBA Antirheumatic Agents Immunology biology.protein Molecular Medicine business Cartilage Diseases |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 318(1) |
| ISSN: | 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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