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Isolation and Enrichment of Human Adipose-derived Stromal Cells for Enhanced Osteogenesis
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Tributyltin engages multiple nuclear receptor pathways and suppresses osteogenesis in bone marrow multipotent stromal

Amelia H Baker1, James Watt1, Cassie K Huang1

  • 1†Department of Medicine and §Department of Orthopaedic Surgery, Boston University School of Medicine, ‡Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts 02118, United States.

Chemical Research in Toxicology
|May 2, 2015
PubMed

Insights

Tributyltin (TBT), an obesogen, suppresses bone formation by activating retinoid X receptors (RXR). This study reveals TBT

Area of Science:

  • Endocrinology
  • Environmental Health
  • Cell Biology

Background:

  • Organotins, like tributyltin (TBT), are environmental obesogens activating peroxisome proliferator-activated receptor γ (PPARγ), a key regulator of fat cell development (adipogenesis).
  • PPARγ activation, seen with diabetes drugs (thiazolidinediones), is linked to bone fractures, suggesting a negative impact on bone quality by promoting fat cell formation while inhibiting bone cell development (osteogenesis) from bone marrow stromal cells (BM-MSCs).
  • Organotins interact with both PPARγ and retinoid X receptors (RXR), indicating potential activation of multiple signaling pathways.

Purpose of the Study:

  • To investigate the role of RXR in tributyltin's (TBT) effects on bone marrow multipotent mesenchymal stromal cells (BM-MSCs).
  • To compare the effects of TBT with specific PPARγ and RXR agonists on BM-MSC differentiation.
  • To determine the primary nuclear receptor pathway through which TBT exerts its bone-suppressing effects.

Main Methods:

  • Treated BMS2 cells and primary mouse BM-MSC cultures with TBT, rosiglitazone (PPARγ agonist), bexarotene, and LG100268 (RXR agonists).
  • Assessed adipogenesis via lipid accumulation and gene expression; evaluated osteogenesis through alkaline phosphatase activity, mineralization, and gene expression.
  • Utilized PPARγ and RXR antagonists (T0070907 and HX531, respectively) to block specific receptor actions and identify the key pathways involved in TBT's effects.

Main Results:

  • TBT induced adipogenic gene expression in BMS2 cells in an RXR-dependent manner.
  • All tested agonists, including TBT, suppressed osteogenesis in primary BM-MSCs.
  • TBT and RXR agonists activated the liver X receptor (LXR) pathway, while rosiglitazone did not; RXR antagonism significantly blocked TBT-induced osteogenesis suppression.

Conclusions:

  • TBT activates multiple nuclear receptor pathways within BM-MSCs.
  • Activation of RXR alone is sufficient to inhibit osteogenesis.
  • TBT primarily suppresses osteogenesis through direct interaction with RXR, highlighting RXR as a critical mediator of TBT's detrimental effects on bone.

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