Activated NF-κB in bone marrow mesenchymal stem cells from systemic lupus erythematosus patients inhibits osteogenic differentiation through downregulating Smad signaling

Stem Cells Dev. 2013 Feb 15;22(4):668-78. doi: 10.1089/scd.2012.0226. Epub 2012 Oct 10.

Abstract

Osteoporosis in patients with systemic lupus erythematosus (SLE) is thought to be the result of accelerated osteoclastogenesis induced by pro-inflammatory cytokines such as tumor necrosis factor (TNF). However, the molecular mechanisms involved in the osteoblastogenesis in SLE patients are not fully understood. We investigated the bone morphogenetic protein-2 (BMP-2)-induced osteoblastic capacity of bone marrow-derived mesenchymal stem cells (BMMSCs) from SLE patients and the TNF signaling system in determining BMP-2-induced regulatory pathways. It showed that the capacity of osteogenic differentiation of BMMSCs from SLE patients was reduced compared with that from healthy controls. The nuclear factor κB (NF-κB) signaling was activated while the BMP/Smad pathway was repressed in BMMSCs from SLE patients. TNF activated NF-κB pathway and inhibited the phosphorylation of Smad 1/5/8 and BMP-2-induced osteoblastic differentiation in BMMSCs from normal controls, while addition of pyrollidine dithiocarbamate (PDTC), an NF-κB inhibitor, to SLE-BMMSCs could partially reverse these effects. Thus, our findings have shown that the activated NF-κB pathway in SLE-BMMSCs inhibits the BMP-2-induced osteoblastic differentiation through BMP/Smad signaling pathway, suggesting that the impaired osteoblastic differentiation may participate in the pathology of osteoporosis in SLE patients.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Agents / pharmacology
  • Bone Marrow Cells* / metabolism
  • Bone Marrow Cells* / pathology
  • Bone Morphogenetic Protein 2 / metabolism
  • Cell Differentiation*
  • Cells, Cultured
  • Down-Regulation*
  • Female
  • Humans
  • Lupus Erythematosus, Systemic* / metabolism
  • Lupus Erythematosus, Systemic* / pathology
  • Male
  • Mesenchymal Stem Cells* / metabolism
  • Mesenchymal Stem Cells* / pathology
  • Middle Aged
  • NF-kappa B / metabolism*
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Osteogenesis*
  • Phosphorylation / drug effects
  • Proline / analogs & derivatives
  • Proline / pharmacology
  • Signal Transduction*
  • Smad Proteins / metabolism*
  • Thiocarbamates / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Antineoplastic Agents
  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • NF-kappa B
  • Smad Proteins
  • Thiocarbamates
  • Tumor Necrosis Factor-alpha
  • prolinedithiocarbamate
  • Proline