There is evidence for hypercortisolemia playing a role in the generation of psychiatric symptoms and for epigenetic variation within hypothalamic-pituitary-adrenal (HPA) axis genes mediating behavioral changes. We tested the hypothesis that expression changes would be induced in Fkbp5 and other HPA axis genes by chronic exposure to corticosterone and that these changes would occur through the epigenetic mechanism of loss or gain of DNA methylation (DNAm). We administered corticosterone (CORT) to C57BL/6J mice via their drinking water for 4 wk and tested for behavioral and physiological changes and changes in gene expression levels using RNA extracted from hippocampus, hypothalamus, and blood for the following HPA genes: Fkbp5, Nr3c1, Hsp90, Crh, and Crhr1. The CORT mice exhibited anxiety-like behavior in the elevated plus maze test. Chronic exposure to CORT also caused a significant decrease in the hippocampal and blood mRNA levels of Nr3c1 and a decrease in Hsp90 in blood and caused an increase in Fkbp5 for all tissues. Differences were seen in Fkbp5 methylation in hippocampus and hypothalamus. To isolate a single-cell type, we followed up with an HT-22 mouse hippocampal neuronal cell line exposed to CORT. After 7 d, we observed a 2.4-fold increase in Fkbp5 expression and a decrease in DNAm. In the CORT-treated mice, we also observed changes in blood DNAm in Fkbp5. Our results suggest DNAm plays a role in mediating effects of glucocorticoid exposure on Fkbp5 function, with potential consequences for behavior.

Subcutaneous implantation of Hunt-Schilling wound chambers in rats induces a wound repair response causing the chamber first to fill with fluid and subsequently with connective tissue. The presence of a type I collagen gel encouraged a more rapid dispersion of cells throughout the chamber but had no effect on the rate of new collagen deposition. Addition of platelet-derived growth factor (PDGF; 50 ng/chamber) to the collagen-filled chambers caused an earlier influx of connective tissue cells, a marked increase in DNA synthesis, and a greater collagen deposition in the chamber during the first 2 wk after implantation. After 3 wk, however, the levels of collagen were similar in PDGFsupplemented and control chambers. Diabetic animals exhibited a decreased rate of repair which was restored to normal by addition of PDGF to the wound chamber. Combinations of PDGF and insulin caused an even more rapid increase in collagen deposition. These results suggest that the levels of various growth factors, particularly PDGF, may be limiting at wound sites and that supplementation of wounds with these factors can accelerate the rate of new tissue formation.

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We identified a large number of differentially expressed genes in the articular cartilage of the MT model. While there was lack of overall identity in cartilage gene expression between the rat models and human OA, several key biological processes were recapitulated in the rat MT OA model.

Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure-activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies.