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Lead induces an osteoarthritis‐like phenotype in articular chondrocytes through disruption of TGF‐β signaling
Author(s) -
Holz Jonathan D.,
Beier Eric,
Sheu TzongJen,
Ubayawardena Resika,
Wang Meina,
Sampson Erik R.,
Rosier Randy N.,
Zuscik Michael,
Puzas J. Edward
Publication year - 2012
Publication title -
journal of orthopaedic research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.22117
Subject(s) - in vivo , chondrocyte , osteoarthritis , in vitro , chemistry , microbiology and biotechnology , cartilage , type ii collagen , pharmacology , signal transduction , matrix (chemical analysis) , medicine , biology , biochemistry , pathology , anatomy , alternative medicine , chromatography
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. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1760–1766, 2012