To address whether mdx mice with haploinsufficiency of utrophin (mdx/utrn+/-) develop more severe skeletal muscle inflammation and fibrosis than mdx mice, to represent a better model for Duchenne muscular dystrophy (DMD), we performed qualitative and quantitative analysis of skeletal muscle inflammation and fibrosis in mdx and mdx/utrn+/- littermates. Inflammation was significantly worse in mdx/utrn+/- quadriceps at age 3 and 6 months and in mdx/utrn+/- diaphragm at age 3 but not 6 months. Fibrosis was more severe in mdx/utrn+/- diaphragm at 6 months, and at this age, mild fibrosis was noted in quadriceps of mdx/utrn+/- but not mdx mice. The findings indicate that utrophin compensates, although insufficiently, for the effects of dystrophin loss with regard to inflammation and fibrosis of both quadriceps and diaphragm muscles in mdx mice. With more severe muscle dystrophy than mdx mice and a longer life span than utrophin-dystrophin-deficient (dko) mice, mdx/utrn+/- mice provide a better mouse model for testing potential therapies for muscle inflammation and fibrosis associated with DMD.

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Pharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib's anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE2 levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.colon cancer ͉ 15-PGDH C olon cancer is the second leading cause of cancer-related death in the United States (1). Strategies for preventing colon cancer have focused on preventing development of colonic adenomas, the pre-malignant tumors that are the precursors of invasive colon cancers (1). Pharmacologic approaches have targeted the inhibition of COX-2, an enzyme that mediates conversion of arachidonic acid to bioactive prostaglandins (PGs), and whose expression is markedly increased in colon cancers (1, 2). Celecoxib, a potent COX-2 inhibitor, decreases colon adenoma development in individuals with familial adenomatous polyposis (3). In individuals with non-familial sporadic colon adenomas, celecoxib reduces by 33%-45% the risk of developing future adenomas, and by 57%-64% the risk of developing adenomas with advanced histology (4, 5). Nonetheless, a significant proportion of individuals exhibit resistance to the colon tumor prevention activity of celecoxib.Recently, we described that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a PG-degrading enzyme, functions as an endogenous inhibitor of the colonic COX-2 pathway and as a colon tumor suppressor gene (6, 7). 15-PGDH is highly expressed in normal colon mucosa, but expression is ubiquitously lost in human colon cancers (6,8). Knocking out the murine 15-PGDH gene markedly sensitizes normally resistant C57BL/6J mice to colon tumor induction by the carcinogen azoxymethane (AOM) (7). In this study, we examined the potential interactions between pharmacologic regulation of colonic PGs by celecoxib and the genetic regulation of colonic PGs by 15-PGDH, and the potential that loss of 15-PGDH as an interacting partner could provide a resista...

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