Abstract
Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid derived from the cytochrome P450 enzymes, 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 selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in a mouse model of periodontitis induced by infection with Aggregatibacter actinomycetemcomitans. 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, receptor activator of nuclear factor-κB/RANK ligand/osteoprotegerin, and the chemokine monocyte chemotactic protein 1 in the gingival tissue without affecting bacterial counts. In addition, downstream kinases p38 and c-Jun N-terminal kinase 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. Together, these results demonstrated that sEH pharmacological inhibition may be of therapeutic value in periodontitis.
Footnotes
- Received November 29, 2016.
- Accepted March 24, 2017.
This work was supported by National Institutes of Health National Institute on Environmental Health Sciences/Superfund Research Program [Grants R01ES002710, P42ES004699, ES025598-01A1, and R00ES024806] and Brazilian funding agencies São Paulo Research Foundation (FAPESP) and National Council for Scientific and Technological Development (CNPq). M.H.N. was supported by Grant 2015/23556-0 (FAPESP) and Grant 303555/2013-0 (CNPq); F.G.H. laboratory is supported by National Institutes of Health [Grants R01DK090492 and R01DK095359]; A.B. is supported by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R00DK100736].
A.B., B.I., S.K.G., F.G.H., and B.D.H. are coinventors on patents related to soluble exposide hydrolase by the University of California; B.I. and B.D.H. are cofounders of Eicosis. The authors declare no competing financial interests.
↵1 C.A.T.-d.-S. and A.B. contributed equally to this work.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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