Abstract
Objective
To define the roles of transforming growth factor α (TGFα) in cartilage degradation.
Methods
Primary rat articular chondrocytes and articular osteochondral explants were cultured with TGFα to assess the effects of TGFα on chondrocyte physiology and phenotype.
Results
TGFα altered chondrocyte morphology through reorganization of the actin cytoskeleton and formation of stress fibers. Expression of anabolic genes, including aggrecan, type II collagen, and cartilage link protein, was reduced in response to TGFα. Proliferation of chondrocytes and formation of articular chondrocyte clusters was stimulated by TGFα. Expression of matrix metalloproteinase 13 and cathepsin C was increased by TGFα. We demonstrated the down‐regulation of Sox9 messenger RNA and protein levels by TGFα. This was associated with reduced levels of phosphorylated and total SOX9 in cartilage explants upon TGFα treatment. In contrast, another growth factor identified in our microarrays, Kitl, had no effects on the chondrocyte parameters tested. To examine correlations between the increased levels of TGFα in experimental knee osteoarthritis (OA) with the levels of TGFα in humans with knee OA, a microarray analysis of mRNA from 13 normal and 12 late‐stage OA cartilage samples was performed. Seven OA samples showed TGFA mRNA levels similar to those in the normal controls, but expression was markedly increased in the other 5 OA samples. These data confirm that TGFA transcript levels are increased in a subset of patients with OA.
Conclusion
This study adds TGFα to the list of dysregulated cytokines present in degrading cartilage in OA. Since TGFα inhibits articular chondrocyte anabolic capacity, increases catabolic factors, and contributes to the development of chondrocyte clusters, TGFα may be a potential target for therapeutic strategies in the treatment of OA.