Delayed bone regeneration and low bone mass in a rat model of insulin-resistant type 2 diabetes mellitus is due to impaired osteoblast function
Delayed bone regeneration and low bone mass in a rat model of insulin-resistant type 2 diabetes mellitus is due to impaired osteoblast function
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DOI：
10.1152/ajpendo.00378.2011
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发表时间：
2011-12-01
影响因子：
5.1
通讯作者：
Hofbauer, Lorenz C.
中科院分区：
文献类型：
--
作者：
Hamann, Christine;Goettsch, Claudia;Hofbauer, Lorenz C.
Hamann C，Goettsch C，Mettelsiefen J，Henkenohann V，Rauner M，Hempel U，Bernhardt R，Fratzl-Zelman N，Roschger P，Rammelt S，Gunther KP，Hofbauer LC.胰岛素抵抗型2型糖尿病大鼠模型中骨再生延迟和低骨量是由于成骨细胞功能受损。Am J Physiol Endocrinol Metab 301：E1220-E1228，2011.首次发表于2011年9月6日; doi：10.1152/ajpendo.00378.2011.-糖尿病患者骨代谢受损;然而，其潜在机制尚不清楚。在这里，我们分析了2型糖尿病对骨生理和再生的影响，使用Zucker糖尿病脂肪（ZDF）大鼠，一种建立的胰岛素抵抗型2型糖尿病大鼠模型。当喂食西方饮食时，ZDF大鼠发生糖尿病和血管并发症。在21周龄的糖尿病大鼠中，与非糖尿病动物相比，股骨远端的骨矿物质密度（BMD）分别降低了22.5%（总）和54.6%（骨小梁），腰椎分别降低了17.2%（总）和20.4%（骨小梁）。通过背散射电子成像测量的BMD分布在糖尿病和非糖尿病大鼠之间没有差异，但组织形态计量学指标评价显示矿化骨体积/组织体积、骨小梁厚度和骨小梁数量较低。糖尿病大鼠的成骨细胞分化基于较低的碱性磷酸酶活性（~ 20%）和矿化基质形成（~ 55%）而受损。此外，成骨细胞特异性基因骨形态发生蛋白-2，RUNX 2，骨钙素和骨桥蛋白的表达降低了40- 80%。基于抗酒石酸酸性磷酸酶染色、孔形成试验和基因分析，破骨细胞生物学未受影响。为了验证这些分子和细胞结果在临床相关模型中的意义，在用四孔板稳定后，在左侧股骨处创建了3 mm的亚临界骨缺损，并通过X射线和微计算机断层扫描分析监测骨再生超过12周。而非糖尿病大鼠填补了57%的缺陷，糖尿病大鼠表现出延迟骨再生，只有21%的缺陷填充。总之，我们确定成骨细胞生成受抑制是2型糖尿病大鼠模型中低骨量和骨再生受损的原因和机制。
Hamann C, Goettsch C, Mettelsiefen J, Henkenjohann V, Rauner M, Hempel U, Bernhardt R, Fratzl-Zelman N, Roschger P, Rammelt S, Gunther KP, Hofbauer LC. Delayed bone regeneration and low bone mass in a rat model of insulin-resistant type 2 diabetes mellitus is due to impaired osteoblast function. Am J Physiol Endocrinol Metab 301: E1220-E1228, 2011. First published September 6, 2011; doi: 10.1152/ajpendo.00378.2011.-Patients with diabetes mellitus have an impaired bone metabolism; however, the underlying mechanisms are poorly understood. Here, we analyzed the impact of type 2 diabetes mellitus on bone physiology and regeneration using Zucker diabetic fatty (ZDF) rats, an established rat model of insulin-resistant type 2 diabetes mellitus. ZDF rats develop diabetes with vascular complications when fed a Western diet. In 21-wk-old diabetic rats, bone mineral density (BMD) was 22.5% (total) and 54.6% (trabecular) lower at the distal femur and 17.2% (total) and 20.4% (trabecular) lower at the lumbar spine, respectively, compared with nondiabetic animals. BMD distribution measured by backscattered electron imaging postmortem was not different between diabetic and nondiabetic rats, but evaluation of histomorphometric indexes revealed lower mineralized bone volume/tissue volume, trabecular thickness, and trabecular number. Osteoblast differentiation of diabetic rats was impaired based on lower alkaline phosphatase activity (-20%) and mineralized matrix formation (-55%). In addition, the expression of the osteoblast-specific genes bone morphogenetic protein-2, RUNX2, osteocalcin, and osteopontin was reduced by 40-80%. Osteoclast biology was not affected based on tartrate-resistant acidic phosphatase staining, pit formation assay, and gene profiling. To validate the implications of these molecular and cellular findings in a clinically relevant model, a subcritical bone defect of 3 mm was created at the left femur after stabilization with a four-hole plate, and bone regeneration was monitored by X-ray and microcomputed tomography analyses over 12 wk. While nondiabetic rats filled the defects by 57%, diabetic rats showed delayed bone regeneration with only 21% defect filling. In conclusion, we identified suppressed osteoblastogenesis as a cause and mechanism for low bone mass and impaired bone regeneration in a rat model of type 2 diabetes mellitus.