RT Journal Article SR Electronic T1 A p38α Selective Mitogen-Activated Protein Kinase Inhibitor Prevents Periodontal Bone Loss JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 56 OP 63 DO 10.1124/jpet.106.112466 VO 320 IS 1 A1 Keith L. Kirkwood A1 Fei Li A1 Jill E. Rogers A1 Jodie Otremba A1 Derek D. Coatney A1 Jaclynn M. Kreider A1 Nisha J. D'Silva A1 Sarvajit Chakravarty A1 Sundeep Dugar A1 Linda S. Higgins A1 Andrew A. Protter A1 Satyanarayana Medicherla YR 2007 UL http://jpet.aspetjournals.org/content/320/1/56.abstract AB In the oral microbial environment, Gram-negative bacterial derived lipopolysaccharide (LPS) can initiate inflammatory bone loss as seen in periodontal diseases. p38 Mitogen-activated protein kinase (MAPK) signaling is critical to inflammatory cytokine and LPS-induced cytokine expression, which may contribute toward periodontal bone loss. The purpose of this proof-of-principle study was to evaluate the ability of an orally active p38α MAPK inhibitor (SD-282) to reduce periopathogenic LPS-induced alveolar bone loss in an experimental rat model. Five groups of Sprague-Dawley rats received one of the following treatments: LPS injected to the palatal gingiva adjacent to the maxillary molars three times per week for 8 weeks, LPS plus two doses of SD-282 (15 or 45 mg/kg) twice daily by oral gavage, or control groups given drug vehicle (1% polyethylene glycol) or SD-282 (45 mg/kg) only. Baseline and 8-week alveolar bone loss was assessed by microcomputed tomography (μCT) and histological examination. LPS induced severe bone loss over this time period, whereas control groups were unchanged from baseline measurements. Both doses of SD-282 showed significant protection from LPS-induced bone loss. Bone area and volumetric analysis of maxillas by μCT indicated significant loss of bone volume with LPS treatment, which was blocked with the p38 inhibitor. Histological examination indicated significantly fewer tartate-resistant acid phosphatase-positive osteoclasts and a significant decrease in interleukin (IL)-6, IL-1β, and tumor necrosis factor α expression in p38 inhibitor-treated groups compared with LPS groups by immunostaining. Results from this in vivo study suggest that orally active p38 MAPK inhibitors can reduce LPS-induced inflammatory cytokine production and osteoclast formation and protect against LPS-stimulated alveolar bone loss. The American Society for Pharmacology and Experimental Therapeutics