A p38 Mitogen‐Activated Protein Kinase Inhibitor Arrests Active Alveolar Bone Loss in a Rat Periodontitis Model

• Published in: Journal of periodontology (1970) 2007-10, Vol.78 (10), p.1992-1998
• Main Authors: Rogers, Jill E., Li, Fei, Coatney, Derek D., Otremba, Jodie, Kriegl, Jaclynn M., Protter, Andrew A., Higgins, Linda S., Medicherla, Satyanarayana, Kirkwood, Keith L.
• Format: Article
• Language: English
• Subjects: Aggregatibacter actinomycetemcomitans; Alveolar bone loss; Alveolar Bone Loss - drug therapy; Alveolar Bone Loss - microbiology; Animals; Biological and medical sciences; cytokines; Dentistry; Diseases of the osteoarticular system; Female; Indoles - pharmacology; Indoles - therapeutic use; Interleukin-1 - antagonists & inhibitors; Interleukin-1 - biosynthesis; lipopolysaccharide; Lipopolysaccharides; Medical sciences; mitogen‐activated protein kinase; Osteoclasts - drug effects; Osteoporosis. Osteomalacia. Paget disease; p38 inhibitor; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; periodontitis; Periodontitis - drug therapy; Periodontitis - microbiology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-3492; 1943-3670
• DOI: 10.1902/jop.2007.070101

Background: Gram‐negative bacterial species, such as Actinobacillus actinomycetemcomitans, contain lipopolysaccharide (LPS) that initiates the innate immune system, resulting in inflammatory alveolar bone loss. LPS activates Toll‐like receptors on membrane surfaces, stimulating many intracellular signaling cascades, including the p38 mitogen‐activated protein kinase (MAPK). Activation of p38 signaling mediates inflammatory cytokine expression, contributing toward osteoclastogenesis and bone loss. The aim of this study was to determine whether the novel, orally active p38 MAPK inhibitor SD282 could arrest progression of LPS‐induced alveolar bone destruction in rats. Methods: Three groups of female Sprague‐Dawley rats received LPS injections to the palatal molar gingiva three times per week for 4 weeks to establish periodontitis. From weeks 5 through 8, two groups received the drug SD282 (N = 14) or 1% polyethylene glycol drug vehicle (N = 14) via oral gavage in addition to LPS injections. The third group continued to receive only LPS injections (N = 8). Microcomputed tomography was used to measure volumetric alveolar bone loss, expressed as bone volume fraction (BVF). Expression of interleukin (IL)‐1 and ‐6 and tumor necrosis factor‐alpha (TNF‐α) was assessed by immunohistochemistry, and osteoclasts were enumerated by tartrate‐resistant acid phosphatase staining. Results: By 4 weeks, severe alveolar bone resorption was seen in LPS‐injected animals. Administration of SD282 significantly blocked additional volumetric bone loss in the LPS‐only versus LPS + SD282 groups (0.37 ± 0.01 BVF versus 0.43 ± 0.01 BVF; P