title: A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis.
abstract: 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.
authors.affiliation: Scios Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA. smediche@scius.jnj.com
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Medicherla
authors.forename: Jing Ying
authors.initials: JY
authors.lastname: Ma
authors.forename: Ruban
authors.initials: R
authors.lastname: Mangadu
authors.forename: Yebin
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Ramona
authors.initials: R
authors.lastname: Almirez
authors.forename: Irene
authors.initials: I
authors.lastname: Kerr
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Stebbins
authors.forename: Gilbert
authors.initials: G
authors.lastname: O'Young
authors.forename: Ann M
authors.initials: AM
authors.lastname: Kapoun
authors.forename: Gregory
authors.initials: G
authors.lastname: Luedtke
authors.forename: Sarvajit
authors.initials: S
authors.lastname: Chakravarty
authors.forename: Sundeep
authors.initials: S
authors.lastname: Dugar
authors.forename: Harry K
authors.initials: HK
authors.lastname: Genant
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Protter
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002357:Cartilage Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D005529:Foot Bones / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases