Lead induces an osteoarthritis-like phenotype in articular chondrocytes through disruption of TGF-β signaling

Lead remains a significant environmental toxin, and we believe we may have identified a novel target of lead toxicity in articular chondrocytes. These cells are responsible for the maintenance of joint matrix, and do so under the regulation of TGF-beta signaling. As lead is concentrated in articular cartilage, we hypothesize that it can disrupt normal chondrocyte phenotype through suppression of TGF-beta signaling. These experiments examine the effects of lead exposure in vivo and in vitro at biologically relevant levels, from 1?nM to 10?mu M on viability, collagen levels, matrix degrading enzyme activity, TGF-beta signaling, and articular surface morphology. Our results indicate that viability was unchanged at levels =100?mu M Pb, but low and high level lead in vivo exposure resulted in fibrillation and degeneration of the articular surface. Lead treatment also decreased levels of type II collagen and increased type X collagen, in vivo and in vitro. Additionally, MMP13 activity increased in a dose-dependent manner. Active caspase 3 and 8 were dose-dependently elevated, and treatment with 10?mu M Pb resulted in increases of 30% and 500%, respectively. Increasing lead treatment resulted in a corresponding reduction in TGF-beta reporter activity, with a 95% reduction at 10 mu M. Levels of phosphoSmad2 and 3 were suppressed in vitro and in vivo and lead dose-dependently increased Smurf2. These changes closely parallel those seen in osteoarthritis. Over time this phenotypic shift could compromise maintenance of the joint matrix. (c) 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:17601766, 2012