STAT-6 mediates TRAIL induced RANK ligand expression in stromal/preosteoblast cells

Kumaran Sundaram, Yuvaraj Sambandam, Sundaravadivel Balasubramanian, Balakrishnan Pillai, Christina Voelkel-Johnson, William L. Ries, Sakamuri V. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Receptor activator of nuclear factor kappa-B ligand (RANKL) is a critical osteoclastogenic factor expressed in bone marrow stromal/osteoblast lineage cells. Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) levels are elevated in pathologic conditions such as multiple myeloma and inflammatory arthritis, and have been positively correlated with osteolytic markers. Osteoprotegerin (OPG) which inhibits osteoclastogenesis is a decoy receptor for RANKL and also known to interact with TRAIL. Herein, we show that TRAIL increases DR5 and DcR1 receptors but no change in the levels of DR4 and DcR2 expression in human bone marrow derived stromal/preosteoblast (SAKA-T) cell line. We further demonstrated that TRAIL treatment significantly decreased OPG mRNA expression. Interestingly, TRAIL treatment induced RANKL mRNA expression in these cells. In addition, TRAIL significantly increased NF-kB and c-Jun N-terminal kinase (JNK) activity. Human transcription factor array screening by real-time RT-PCR identified TRAIL up-regulation of the signal transducers and activators of the transcription (STAT)-6 expression in SAKA-T cells. TRAIL stimulation induced p-STAT-6 expression in human bone marrow derived primary stromal/preosteoblast cells. Confocal microscopy analysis further revealed p-STAT-6 nuclear localization in SAKA-T cells. Chromatin immunoprecipitation (ChIP) assay confirmed p-STAT-6 binding to the hRANKL gene distal promoter region. In addition, siRNA suppression of STAT-6 expression inhibits TRAIL increased hRANKL gene promoter activity. Thus, our results suggest that TRAIL induces RANKL expression through a STAT-6 dependent transcriptional regulatory mechanism in bone marrow stromal/preosteoblast cells.

Original languageEnglish (US)
Pages (from-to)137-144
Number of pages8
JournalBone
Volume71
DOIs
StatePublished - Feb 1 2015

Keywords

  • RANK ligand
  • STAT-6
  • Stromal/preosteoblasts
  • TRAIL

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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    Sundaram, K., Sambandam, Y., Balasubramanian, S., Pillai, B., Voelkel-Johnson, C., Ries, W. L., & Reddy, S. V. (2015). STAT-6 mediates TRAIL induced RANK ligand expression in stromal/preosteoblast cells. Bone, 71, 137-144. https://doi.org/10.1016/j.bone.2014.10.016