Functional characterization of an orphan nuclear receptor, Rev-ErbAalpha, in chondrocytes and its potential role in osteoarthritis

To evaluate the expression and function of the orphan nuclear receptor Rev-ErbAalpha in articular cartilage and to investigate its role in osteoarthritis (OA).

Expression of Rev-ErbAalpha was analyzed at both the messenger RNA and protein levels in human and bovine articular cartilage and chondrocytes by real-time polymerase chain reaction (TaqMan) and immunocytochemical techniques. The effects of cartilage catabolic and anabolic agents on the expression of Rev-ErbAalpha were evaluated by TaqMan analysis. Overexpression was achieved by either adenoviral transduction or treatment with a peroxisome proliferator-activated receptor alpha agonist, whereas expression was suppressed by antisense oligonucleotides.

Among the 48 known nuclear receptors, Rev-ErbAalpha was found to be the most highly expressed in OA cartilage. It is known to function as a transcription repressor. Treatment of articular chondrocytes with known catabolic agents resulted in the induction of Rev-ErbAalpha, whereas stimulation with anabolic agents led to a decrease in expression. Overexpression of the nuclear receptor was associated with an increase in the expression of matrix-degrading enzymes such as matrix metalloproteinase 13 and aggrecanase. In contrast, a decrease in Rev-ErbAalpha expression led to a concomitant reduction in the activity of matrix-degrading enzymes.

This study is the first to demonstrate that Rev-ErbAalpha is highly expressed in OA articular chondrocytes and that its expression is modulated by known cartilage catabolic and anabolic stimuli. We also demonstrated that modulation of Rev-ErbAalpha expression in chondrocytes may be a novel means of regulating the expression and production of multiple matrix-degrading enzymes. These observations suggest that Rev-ErbAalpha may be a novel therapeutic target for OA.