Lead induces chondrogenesis and alters transforming growth factor-β and bone morphogenetic protein signaling in mesenchymal cell populations

Michael J. Zuscik, Lin Ma, Taylor Buckley, J. Edward Puzas, Hicham Drissi, Edward M. Schwarz, Regis J. O'Keefe

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Background: It has been established that skeletal growth is stunted in lead-exposed children. Because chondrogenesis is a seminal step during skeletal development, elucidating the impact of Pb on this process is the first step toward understanding the mechanism of Pb toxicity in the skeleton. Objectives: The aim of this study was to test the hypothesis that Pb alters chondrogenic commitment of mesenchymal cells and to assess the effects of Pb on various signaling pathways. Methods: We assessed the influence of Pb on chondrogenesis in murine limb bud mesenchymal cells (MSCs) using nodule formation assays and gene analyses. The effects of Pb on transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling was studied using luciferase-based reporters and Western analyses, and luciferase-based assays were used to study cyclic adenosine monophosphate response element binding protein (CREB), β-catenin, AP-1, and nuclear factor-kappa B (NF-κB) signaling. We also used an ectopic bone formation assay to determine how Pb affects chondrogenesis in vivo. Results: Pb-exposed MSCs showed enhanced basal and TGF-β/BMP induction of chondrogenesis, evidenced by enhanced nodule formation and up-regulation of Sox-9, type 2 collagen, and aggrecan, all key markers of chondrogenesis. We observed enhanced chondrogenesis during ectopic bone formation in mice preexposed to Pb via drinking water. In MSCs, Pb enhanced TGF-β but inhibited BMP-2 signaling, as measured by luciferase reporter assays and Western analyses of Smad phosphorylation. Although Pb had no effect on basal CREB or Wnt/β-catenin pathway activity, it induced NFκB signaling and inhibited AP-1 signaling. Conclusions: The in vitro and in vivo induction of chondrogenesis by Pb likely involves modulation and integration of multiple signaling pathways including TGF-β, BMP, AP-1, and NFκB.

Original languageEnglish
Pages (from-to)1276-1282
Number of pages7
JournalEnvironmental Health Perspectives
Volume115
Issue number9
DOIs
StatePublished - Sep 2007

Keywords

  • BMP signaling
  • Chondrogenesis
  • Lead
  • Mesenchymal stem cells
  • TGF-β signaling

Fingerprint

Dive into the research topics of 'Lead induces chondrogenesis and alters transforming growth factor-β and bone morphogenetic protein signaling in mesenchymal cell populations'. Together they form a unique fingerprint.

Cite this