Introduction: Articular cartilage degeneration is a hallmark of osteoarthritis (OA). We sought to identify dysregulated genes in degenerating cartilage and hypothesized that altered growth factor expression causes cartilage degradation in OA. 
 Methods: Genome-wide microarray analysis of RNA harvested directly from sham (control) and degenerating articular cartilage was performed using our previously characterized pre-clinical rat model of knee OA1. Known OA genes were validated using RNA samples (real-time PCR) and histological sections (immunofluorescence) from independent animals. Functional studies in chondrocytes and articular cartilage explants investigated the effects of one identified factor (transforming growth factor alpha (TGF-α)) on cartilage degeneration. The effects of TGF-α on primary chondrocyte morphology, proliferation, gene expression, and SOX9 transcription factor expression were assessed. 
 Results: Dysregulated gene expression profiles in degenerating cartilage included known OA genes2. Microarray expression profiles were consistently validated at RNA and protein levels by alternative methods. Several genes previously unstudied in OA cartilage were upregulated, including growth factors (e.g. TGF-α and kit ligand), cell surface receptors (e.g. endothelin type A receptor), and proteases (e.g. cathepsin S). Functional studies demonstrated that TGF-α alters chondrocyte morphology through re-organization of the actin cytoskeleton. TGF-α also stimulated primary chondrocyte proliferation and chondrocyte cluster formation in cartilage explants. Chondrocyte expression of anabolic genes and total collagen protein levels were reduced by TGF-α, while expression of catabolic factors increased. Finally, TGF-α reduced both the expression of total SOX9 and levels of phosphorylated (active) SOX9. 
 Conclusions: Our microarray study identified numerous factors previously unstudied in OA cartilage, including increased levels of TGF-α. Functional studies determined that TGF-α promotes cartilage degeneration through chondrocyte proliferation and catabolic factor expression. Further, TGF-α inhibits chondrocyte anabolism, likely through a mechanism involving suppression of SOX9.