TRPV2-induced Ca(2+)-calcineurin-NFAT signaling regulates differentiation of osteoclast in multiple myeloma.
TRPV2-induced Ca(2+)-calcineurin-NFAT signaling regulates differentiation of osteoclast in multiple myeloma.
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DOI：
10.1186/s12964-018-0280-8
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发表时间：
2018-10-16
期刊：
影响因子：
--
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Bai H;Zhu H;Yan Q;Shen X;Lu X;Wang J;Li J;Chen L
骨髓瘤性骨病（Myeloma bone disease，MBD）可引起骨破坏，并通过刺激成骨细胞分化而使骨髓微环境中Ca ~（2+）浓度升高。然而，在多发性骨髓瘤（MM）进展中MBD和高效Ca 2+刺激之间的关系以及可能的调控机制尚不清楚。在这里，我们报告了非选择性阳离子通道瞬时受体电位香草酸2（TRPV 2）中起着功能性作用的Ca 2+振荡和破骨细胞genesis.MethodsTo调查TRPV 2在MM中的表达，我们分析了公开的MM数据集，并进行免疫组化MM患者。分析TRPV 2表达水平与破骨细胞相关细胞因子的相关性。Fluo-4染色和ELISA检测TRPV 2对细胞内Ca ~（2+）和细胞因子的调节作用。采用Western blotting和ChIP方法研究TRPV 2诱导成骨细胞分化的信号通路。采用Real-time PCR、Western blotting、ELISA和抗酒石酸酸性磷酸酶（TRAP）染色等方法检测TRPV 2抑制剂对破骨细胞生成的影响。TRPV 2通过Ca 2 +-钙调神经磷酸酶-NFAT信号通路调节核因子-κB配体（RANKL）依赖性骨细胞分化的机制。临床相关性，全身给药SKF 96365可以减弱MM诱导的破骨细胞形成在vitro.ConclusionsOur研究揭示了TRPV 2的可能作用，这增强了MBD，这表明通过阻断TRPV 2通道靶向骨细胞MM细胞的相互作用可能提供了一个有前途的治疗策略在MM。
BackgroundMyeloma bone disease (MBD) can cause bone destruction and increase the level of Ca2+concentration in the bone marrow microenvironment by stimulating osteoclastic differentiation. Nevertheless, the relationships between MBD and highly efficient stimuli of Ca2+in multiple myeloma (MM) progression, and possible regulatory mechanisms are poorly defined. Here, we reported that the nonselective cation channel transient receptor potential vanilloid 2 (TRPV2) plays a functional role in Ca2+oscillations and osteoclastogenesis.MethodsTo investigate the expression of TRPV2 in MM, we analyzed publicly available MM data sets and performed immunohistochemistry in MM patients. The correlations between TRPV2 expression levels and osteoclast-related cytokines were analyzed. Fluo-4 staining and ELISA assays were used to assess the regulated function of TRPV2 in intracellular Ca2+and cytokines. Western blotting and Chromatin immunoprecipitation (ChIP) assays were performed to explore the signaling pathway of TRPV2-induced osteoclastic differentiation. Real-time PCR, Western blotting, ELISA and tartrate-resistant acid phosphatase (TRAP) staining were performed to detect the biological effects of TRPV2 inhibitor on osteoclastogenesis.ResultsThe functional expression of TRPV2, involved in the osteolysis through gating the calcium influx, was changed in the MM cells cultured in a high Ca2+environment. Mechanistically, TRPV2 modulates nuclear factor-κB ligand (RANKL)-dependent osteoclastic differentiation through the Ca2+-calcineurin-NFAT signaling pathway. Of clinical relevance, systemic administration with SKF96365 could attenuate the MM-induced osteoclast formation in vitro.ConclusionsOur study uncovers the possible roles of TRPV2, which enhances MBD, suggesting that targeting osteocyte-MM cells interactions through blockade of TRPV2 channel may provide a promising treatment strategy in MM.
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