Tributyltin Engages Multiple Nuclear Receptor Pathways and Suppresses Osteogenesis in Bone Marrow Multipotent Stromal Cells
Tributyltin Engages Multiple Nuclear Receptor Pathways and Suppresses Osteogenesis in Bone Marrow Multipotent Stromal Cells
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DOI：
10.1021/tx500433r
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发表时间：
2015-06-01
影响因子：
4.1
通讯作者：
Schlezinger, Jennifer J.
中科院分区：
文献类型：
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作者：
Baker, Amelia H.;Watt, James;Schlezinger, Jennifer J.
有机素是环境致肥类污染物的成员，因为它们激活过氧化物酶体增殖激活受体γ (PPAR γ)，脂肪形成的重要调节因子。暴露于噻唑烷二酮（PPAR γ配体用于治疗2型糖尿病）与骨折增加有关。骨质量下降可能是由于PPAR γ在促进脂肪生成的同时抑制骨髓多能间充质基质细胞（BM-MSC）的成骨作用。我们假设三丁基锡（TBT）可能是脑基质间充质干细胞分化的有效调节剂和骨形成的负调节因子。有机锡素与PPAR γ和类视黄醇X受体（RXR）相互作用，表明它们激活多种核受体途径。为了研究RXR在TBT作用中的作用，我们将PPAR γ（罗格列酮）和RXR（贝沙罗汀，LG100268）激动剂与TBT在BMS2细胞和原代小鼠BM-MSC培养中的作用进行了比较。在BMS2细胞中，TBT以rxr依赖的方式诱导Fabp4、Abca1和Tgm2的表达。基于碱性磷酸酶活性、矿化和成骨细胞相关基因表达的降低，所有激动剂都抑制了原代小鼠BM-MSC培养中的成骨。罗格列酮和TBT通过脂质积累和脂肪细胞相关基因的表达强烈激活脂肪形成，而RXR激动剂则没有。将这些分析扩展到其他RXR异源二聚体表明，TBT和RXR激动剂激活了肝脏X受体途径，而罗格列酮则没有。应用PPAR γ拮抗剂（T0070907）或RXR拮抗剂（HX531）可显著降低罗格列酮诱导的骨结节形成抑制。只有RXR拮抗剂能显著降低LG100268和tbt诱导的骨抑制。RXR拮抗剂还能抑制LG100268和tbt诱导的原代BM-MSC培养中LXR靶基因Abca1的表达。这些结果提供了新的证据，证明TBT激活了BM-MSCs的多种核受体通路，激活RXR足以抑制成骨，TBT主要通过与RXR的直接相互作用来抑制成骨。
Organotins are members of the environmental obesogen class of contaminants because they activate peroxisome proliferator-activated receptor gamma (PPAR gamma), the essential regulator of adipogenesis. Exposure to thiazolidinediones (PPAR gamma ligands used to treat type 2 diabetes) is associated with increased fractures. Diminished bone quality likely results from PPAR gamma's role in promoting adipogenesis while suppressing osteogenesis of bone marrow multipotent mesenchymal stromal cells (BM-MSC). We hypothesized that tributyltin (TBT) would be a potent modifier of BM-MSC differentiation and a negative regulator of bone formation. Organotins interact with both PPAR gamma and retinoid X receptors (RXR), suggesting that they activate multiple nuclear receptor pathways. To investigate the role of RXR in the actions of TBT, the effects of PPAR gamma (rosiglitazone) and RXR (bexarotene, LG100268) agonists were compared to the effects of TBT in BMS2 cells and primary mouse BM-MSC cultures. In BMS2 cells, TBT induced the expression of Fabp4, Abca1, and Tgm2 in an RXR-dependent manner. All agonists suppressed osteogenesis in primary mouse BM-MSC cultures, based on decreased alkaline phosphatase activity, mineralization, and expression of osteoblast-related genes. While rosiglitazone and TBT strongly activated adipogenesis, based on lipid accumulation and expression of adipocyte-related genes, the RXR agonists did not. Extending these analyses to other RXR heterodimers showed that TBT and the RXR agonists activated the liver X receptor pathway, whereas rosiglitazone did not. Application of either a PPAR gamma antagonist (T0070907) or an RXR antagonist (HX531) significantly reduced rosiglitazone-induced suppression of bone nodule formation. Only the RXR antagonist significantly reduced LG100268- and TBT-induced bone suppression. The RXR antagonist also inhibited LG100268- and TBT-induced expression of Abca1, an LXR target gene, in primary BM-MSC cultures. These results provide novel evidence that TBT activates multiple nuclear receptor pathways in BM-MSCs, activation of RXR is sufficient to suppress osteogenesis, and TBT suppresses osteogenesis largely through its direct interaction with RXR.