Soluble Epoxide Hydrolase Pharmacological Inhibition Decreases Alveolar Bone Loss

Objectives: Epoxyeicosatrienoic acids (EETs), the metabolites of arachidonic acid derived from the cytochrome P450 (CYP450) epoxygenases, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs but not their diols, have anti-inflammatory properties and inhibition of sEH might provide protective effects against inflammatory bone loss. Thus, in the present study, we tested the selected sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) mouse model of periodontitis induced by A. actinomycetemcomitans infection.
Methods: Mice were infected with A. actinomycetemcomitans, and divided into groups that were treated with TPPU. The animals were sacrificed, the jaws were analyzed for bone resorption by morphometry. Immuno-inflammatory markers in the gingival tissue were analyzed by western blotting.
Results: Oral treatment of wild type mice with TPPU and sEH knockout (KO) animals showed reduced bone loss induced by A. actinomycetemcomitans. This was associated with decreased expression of key osteoclastogenic molecules RANK/RANKL/OPG and the chemokine MCP-1 in the gingival tissue without affecting bacterial counts. In addition, downstream kinases p38 and JNK known to be activated in response to inflammatory signals were abrogated after TPPU treatment or in sEH KO mice. Moreover, endoplasmic reticulum stress was elevated in periodontal disease but was abrogated after TPPU treatment and in sEH knockout mice.
Conclusions: Together, these results demonstrated that sEH pharmacological inhibition may be of therapeutic value in periodontitis.