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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A p38 Selective Mitogen-Activated Protein Kinase Inhibitor Prevents Periodontal Bone Loss

Department of Periodontics and Oral Medicine (K.L.K., F.L., J.E.R., J.O., D.D.C., N.J.D.), Department of Pathology (N.J.D.), and Orthopedics Research Laboratory (J.M.K.), University of Michigan, Ann Arbor, Michigan; and Scios, Inc., Fremont, California (S.C., L.S.H., S.D., A.A.P., S.M.)

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 p38 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-1, and tumor necrosis factor 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.

Address correspondence to: Dr. Keith L. Kirkwood, University of Michigan, Department of Periodontics and Oral Medicine, 1011 N. University Ave., Ann Arbor, MI 48109-1078. E-mail: klkirk{at}umich.edu

This article has been cited by other articles:

				C.S. Patil and K.L. Kirkwood p38 MAPK Signaling in Oral-related Diseases Journal of Dental Research, September 1, 2007; 86(9): 812 - 825. [Abstract] [Full Text] [PDF]