The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes.
The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes.
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DOI：
10.1016/j.trsl.2012.08.006
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Umpierrez GE
中科院分区：
文献类型：
--
作者：
Beck GR Jr;Khazai NB;Bouloux GF;Camalier CE;Lin Y;Garneys LM;Siqueira J;Peng L;Pasquel F;Umpierrez D;Smiley D;Umpierrez GE
噻唑烷二酮 (TZD) 治疗与骨折风险增加有关。对啮齿动物的研究建立了一个模型，其中 TZD 引起的骨质量下降是由于成骨细胞和脂肪细胞之间对共同前体细胞的谱系定向竞争，导致成骨细胞数量减少。我们的目标是研究 TZD 暴露对非糖尿病受试者和 2 型糖尿病患者的体外和体内原代人骨髓基质细胞 (hBMSC) 成骨细胞-脂肪细胞谱系测定的影响。我们的实验设计包括两个阶段。第一阶段：TZD 对非糖尿病受试者中 hBMSC 分化为成骨细胞和脂肪细胞影响的体外研究。第 2 阶段：一项随机安慰剂对照试验，通过 2 型糖尿病患者的脂肪细胞/成骨细胞集落形成单位测定，确定 6 个月的吡格列酮体内治疗对 hBMSC 分化的影响。在体外，TZD（吡格列酮和罗格列酮）增强 hBMSC 的脂肪生成，同时不会改变成骨细胞的分化和/或功能（通过碱性磷酸酶活性、基因表达和矿化测量）。 TZD 增强脂肪生成的能力发生在分化过程的特定时间/阶段，并且用 TZD 预处理并没有进一步增强脂肪生成。在体内，六个月的 TZD 治疗减少了 2 型糖尿病患者的成骨细胞前体细胞，增加了脂肪细胞前体细胞，并增加了总集落数。我们的结果表明，体外 TZD 暴露可有效刺激脂肪生成，但不会直接改变成骨细胞分化/矿化或 hBMSC 的谱系定向。然而，与安慰剂相比，2 型糖尿病患者的 TZD 治疗导致 hBMSC 的成骨细胞生成减少，这表明对成骨细胞有间接的负面影响，这表明 TZD 可能通过另一种模型负向调节骨质量。
Thiazolidinedione (TZD) therapy has been associated with increased risk of bone fractures. Studies in rodents have led to a model in which decreased bone quality in response to TZDs is due to a competition of lineage commitment between osteoblasts and adipocytes for a common precursor cell resulting in decreased osteoblast numbers. Our goal was to investigate the effects of TZD exposure on osteoblast-adipocyte lineage determination from primary human bone marrow stromal cells (hBMSCs) both in vitro and in vivo from non-diabetic subjects and patients with type 2 diabetics. Our experimental design included two phases. Phase 1: An in vitro study of TZDs effects on hBMSCs differentiation into osteoblasts and adipocytes in non-diabetic subjects. Phase 2: a randomized placebo controlled trial to determine the effects of six month pioglitazone treatment in vivo on hBMSC differentiation using adipocyte/osteoblast colony forming unit assays in patients with type 2 diabetes. In vitro, TZDs (pioglitazone and rosiglitazone) enhanced adipogenesis of hBMSCs while neither altered osteoblast differentiation and/or function as measured by alkaline phosphatase activity, gene expression, and mineralization. The ability of TZDs to enhance adipogenesis occurred at a specific time/stage of the differentiation process and pre-treating with TZDs did not further enhance adipogenesis. In vivo, six month TZD treatment decreased osteoblast precursors, increased adipocyte precursors, and increased total colony number in patients with type 2 diabetes. Our results indicate that TZD exposure in vitro potently stimulates adipogenesis but does not directly alter osteoblast differentiation/mineralization or lineage commitment from hBMSCs. TZD-treatment in type 2 diabetic patients however results in decreased osteoblastogenesis from hBMSCs compared to placebo indicating an indirect negative effect on osteoblasts suggesting an alternative model by which TZDs might negatively regulate bone quality.
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