title: Lead induces an osteoarthritis-like phenotype in articular chondrocytes through disruption of TGF-β signaling.
abstract: 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-β signaling. As lead is concentrated in articular cartilage, we hypothesize that it can disrupt normal chondrocyte phenotype through suppression of TGF-β signaling. These experiments examine the effects of lead exposure in vivo and in vitro at biologically relevant levels, from 1 nM to 10 µM on viability, collagen levels, matrix degrading enzyme activity, TGF-β signaling, and articular surface morphology. Our results indicate that viability was unchanged at levels ≤100 µM 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 µM Pb resulted in increases of 30% and 500%, respectively. Increasing lead treatment resulted in a corresponding reduction in TGF-β reporter activity, with a 95% reduction at 10µM. 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.
authors.affiliation: Department of Orthopaedics, University of Rochester School of Medicine and Dentristry, Rochester, NY 14642, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Holz
authors.forename: Eric
authors.initials: E
authors.lastname: Beier
authors.forename: Tzong-Jen
authors.initials: TJ
authors.lastname: Sheu
authors.forename: Resika
authors.initials: R
authors.lastname: Ubayawardena
authors.forename: Meina
authors.initials: M
authors.lastname: Wang
authors.forename: Erik R
authors.initials: ER
authors.lastname: Sampson
authors.forename: Randy N
authors.initials: RN
authors.lastname: Rosier
authors.forename: Michael
authors.initials: M
authors.lastname: Zuscik
authors.forename: J Edward
authors.initials: JE
authors.lastname: Puzas
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002645:Chickens; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D007854:Lead / Q000633:toxicity*; D010003:Osteoarthritis / Q000139:chemically induced*; D010641:Phenotype; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D023382:Toxicity Tests, Acute; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D007854:Lead