Functional characterization of an orphan nuclear receptor, Rev-ErbAalpha, in chondrocytes and its potential role in osteoarthritis.
OBJECTIVE
To evaluate the expression and function of the orphan nuclear receptor Rev-ErbAalpha in articular cartilage and to investigate its role in osteoarthritis (OA).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Chaturvedi
P
P
Microbial, Musculoskeletal, and Proliferative Diseases, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. priya.2.chaturvedi@gsk.com
Pratta
M
M
Steplewski
K
K
Connor
J
J
Kumar
S
S
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071116:ADAMTS5 Protein; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002356:Cartilage / Q000166:cytology / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D016376:Oligonucleotides, Antisense; D010003:Osteoarthritis / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; C064353:NR1D1 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D014212:Tretinoin; D007334:Insulin-Like Growth Factor I; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D053509:Matrix Metalloproteinase 13