Insulin-dependent diabetes mellitus decreases osteoblastogenesis associated with the inhibition of Wnt signaling through increased expression of Sost and Dkk1 and inhibition of Akt activation
Insulin-dependent diabetes mellitus decreases osteoblastogenesis associated with the inhibition of Wnt signaling through increased expression of Sost and Dkk1 and inhibition of Akt activation
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DOI：
10.3892/ijmm.2011.697
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发表时间：
2011-09-01
影响因子：
5.4
通讯作者：
Tsukamoto, Ikuyo
中科院分区：
文献类型：
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作者：
Hie, Mamiko;Iitsuka, Natsumi;Tsukamoto, Ikuyo
胰岛素依赖型糖尿病（IDDM）已知与骨质减少风险增加相关。然而，IDDM诱导的骨改变的细胞和分子机制还不清楚。本研究采用链脲佐菌素（STZ）致糖尿病大鼠，观察了胰岛素依赖性糖尿病（IDDM）对骨代谢的影响。4周后，糖尿病大鼠出现骨丢失，骨钙素、胰岛素样生长因子-I（IGF-I）和骨碱性磷酸酶（ALP）活性降低，骨抗酒石酸酸性磷酸酶（TRAP）和组织蛋白酶K活性正常，尿脱氧吡啶啉（Dpd）排泄正常。组织学分析显示胫骨近端干骺端成骨细胞数量减少，破骨细胞数量正常。ALP、Osteoclacin和胶原mRNA的表达降低与Runx相关转录因子2（Runx 2）、Osterix和无远端同源框5（Dlx 5）的表达降低以及骨形态发生蛋白2（BMP 2）的表达不变相关。Runx 2、磷酸化糖原合成酶激酶3 β（GSK 3 β）、活性β-连环蛋白和β-连环蛋白的蛋白水平下降。Akt的激活受到抑制。Win信号传导抑制剂骨质疏松症（Sost）和Dickkopf 1（Dkk 1）的mRNA和蛋白水平增加。IGF-I和IGF-I受体（IGF-IR）的mRNA表达受到抑制。在糖尿病大鼠骨中观察到的这些变化可通过胰岛素治疗逆转，但不能通过IGF-I治疗使循环IGF-I水平正常化。这些结果表明，胰岛素缺乏在胰岛素依赖型糖尿病减少成骨细胞与抑制Wnt信号通过增加表达的Sost和Dkk 1和抑制Akt的激活。
Insulin-dependent diabetes mellitus (IDDM) is known to be associated with an increased risk of osteopenia. However, the cellular and molecular mechanisms for IDDM-induced alterations of the bone are not well understood. The effects of IDDM on bone metabolism were investigated using rats rendered diabetic by an injection of streptozotocin (STZ). After 4 weeks, the diabetic rats exhibited bone loss, low levels of osteocalcin, insulin-like growth factor-I (IGF-I) and bone alkaline phosphatase (ALP) activity with normal levels of bone tartrate-resistant acid phosphatase (TRAP) and cathepsin K activity, and urinary excretion of deoxypyridinoline (Dpd). Histological analysis showed a decrease in the number of osteoblasts with a normal number of osteoclasts in the metaphysis of the proximal tibia. The decreased expression of ALP, osteoclacin and collagen mRNA was associated with a decrease in the expression of runt-related transcription factor 2 (Runx2), Osterix and distal-less homeobox 5 (Dlx5) and an unaltered expression of bone morphogenic protein-2 (BMP2). The protein levels of Runx2, phosphorylated glycogen synthase kinase 3 beta (GSK3 beta), active beta-catenin and beta-catenin decreased. The activation of Akt was inhibited. The mRNA and protein levels of sclerosteosis (Sost) and Dickkopf 1 (Dkk1), inhibitors of Win signaling, increased. The mRNA expression of IGF-I and the IGF-I receptor (IGF-IR) was suppressed. These changes observed in the bone of diabetic rats were reversed by treatment with insulin, but not by normalization of the circulating IGF-I levels by treatment with IGF-I. These results suggest that insulin-deficiency in IDDM decreases osteoblastogenesis associated with inhibition of Wnt signaling through the increased expression of Sost and Dkk1 and the inhibition of Akt activation.