Activation of the peroxisome proliferator-activated receptor alpha pathway potentiates interleukin-1 receptor antagonist production in cytokine-treated chondrocytes.

OBJECTIVE: To determine whether peroxisome proliferator-activated receptor alpha (PPARalpha) agonists protect chondrocytes against the effects of interleukin-1beta (IL-1beta). METHODS: PPARalpha expression and function in cultured rabbit articular chondrocytes were studied by Northern blotting, electrophoretic mobility shift assay, and transient expression of a luciferase reporter construct bearing the human IL-1 receptor antagonist (Il-1Ra) gene promoter. Chondrocytes were incubated in vitro with IL-1beta alone or in combination with CloFibrate (CloF) or other PPAR ligands. Proteoglycans were evaluated by 35S-sulfate incorporation, matrix metalloproteinase (MMP) levels were assessed by zymography and enzyme-linked immunosorbent assay (ELISA), and MMP messenger RNA (mRNA) levels were measured by Northern blotting and real-time reverse transcriptase-polymerase chain reaction. IL-1beta and IL-1Ra soluble contents were measured by ELISA. RESULTS: CloF counteracted IL-1beta-induced 35S-proteoglycan degradation, gelatinolytic activity, and MMP-1, -3, and -13 mRNA expression. CloF also maximized IL-1beta-induced endogenous production of soluble IL-1Ra (sIL-1Ra). This stimulating effect on IL-1Ra gene expression was shown, by transient expression assay, to be transcriptional. Inhibition of sIL-1Ra expression by a specific small interfering RNA suppressed the effect of CloF on IL-1beta-induced MMP expression. The stimulatory effect of CloF was enhanced by cotransfection with wild-type PPARalpha and abolished by a dominant-negative PPARalpha mutant. Fenofibrate and WY-14643 displayed a similar stimulating effect on the IL-1Ra promoter, while rosiglitazone did not. Two PPAR response elements, an NF-kappaB-binding site, and a CCAAT/enhancer binding protein-binding site were identified in the IL-1Ra promoter. All 4 sites were necessary for mediation of the effects of CloF. CONCLUSION: Our findings support the notion that there is a PPARalpha-dependent mechanism that inhibits IL-1beta function in chondrocytes, which operates via an increase in sIL-1Ra production.

Antidiabetic actions of estrogen: insight from human and genetic mouse models.

There is increasing evidence both in humans and rodents linking the endogenous estrogen 17b-estradiol (E2) to the maintenance of glucose homeostasis. Postmenopausal women develop visceral obesity and insulin resistance and are at increased risk for type 2 diabetes mellitus, but hormone replacement therapy leads to a reduction in the incidence of diabetes. In various spontaneous rodent models of type 2 diabetes, female rodents are protected against hyperglycemia unless they are ovariectomized, and E2 perfusion reverses diabetes in male rodents. Finally, the study of transgenic mice and mice with genetic alteration of E2 secretion or E2 action has shed light on the antidiabetic properties of E2 at a tissue-specific level. Thus, E2 secretion and action in rodents seems to be implicated 1) in adipose tissue biology and the prevention of obesity, 2) in the stimulation of liver fatty acid metabolism and suppression of hepatic glucose production, and 3) in the protection of pancreatic b-cell function/survival and insulin secretion in conditions of oxidative stress.