A p38 mitogen-activated protein kinase inhibitor arrests active alveolar bone loss in a rat periodontitis model.
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-alpha) 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 < 0.01). Significant reductions in IL-1beta (P < 0.01 ), TNF-alpha (P < 0.05), and osteoclast formation (P < 0.01) occurred in the presence of SD282.


CONCLUSIONS
An orally active p38 MAPK inhibitor reduced LPS-induced inflammatory cytokine expression, osteoclastogenesis, and alveolar bone loss in rats. Within the limits of the current study, SD282 arrested periodontal disease progression, thus highlighting the therapeutic potential of this novel class of inhibitors.
Rogers
Jill E
JE
Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA.
Li
Fei
F
Coatney
Derek D
DD
Otremba
Jodie
J
Kriegl
Jaclynn M
JM
Protter
T Andrew A
TA
Higgins
Linda S
LS
Medicherla
Satyanarayana
S
Kirkwood
Keith L
KL
D016976:Aggregatibacter actinomycetemcomitans; D016301:Alveolar Bone Loss / Q000188:drug therapy* / Q000382:microbiology; D000818:Animals; D005260:Female; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008070:Lipopolysaccharides; D010010:Osteoclasts / Q000187:drug effects; D010518:Periodontitis / Q000188:drug therapy* / Q000382:microbiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D007211:Indoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C514526:indole-5-carboxamide; D048051:p38 Mitogen-Activated Protein Kinases