Raehtz Sandi, Bierhalter Hayley, Schoenherr Daniel, Parameswaran Narayanan, McCabe Laura R
Department of Physiology, Michigan State University, East Lansing, Michigan 48824.
Department of Radiology, Michigan State University, East Lansing, Michigan 48824.
Endocrinology. 2017 Jul 1;158(7):2086-2101. doi: 10.1210/en.2016-1821.
Estrogen deficiency after menopause is associated with rapid bone loss, osteoporosis, and increased fracture risk. Type 1 diabetes (T1D), characterized by hypoinsulinemia and hyperglycemia, is also associated with bone loss and increased fracture risk. With better treatment options, T1D patients are living longer; therefore, the number of patients having both T1D and estrogen deficiency is increasing. Little is known about the mechanistic impact of T1D in conjunction with estrogen deficiency on bone physiology and density. To investigate this, 11-week-old mice were ovariectomized (OVX), and T1D was induced by multiple low-dose streptozotocin injection. Microcomputed tomographic analysis indicated a marked reduction in trabecular bone volume fraction (BVF) in T1D-OVX mice (82%) that was far greater than the reductions (50%) in BVF in either the OVX and T1D groups. Osteoblast markers, number, and activity were significantly decreased in T1D-OVX mice, to a greater extent than either T1D or OVX mice. Correspondingly, marrow adiposity was significantly increased in T1D-OVX mouse bone. Bone expression analyses revealed that tumor necrosis factor (TNF)-α levels were highest in T1D-OVX mice and correlated with bone loss, and osteoblast and osteocyte death. In vitro studies indicate that estrogen deficiency and high glucose enhance TNF-α expression in response to inflammatory signals. Taken together, T1D combined with estrogen deficiency has a major effect on bone inflammation, which contributes to suppressed bone formation and osteoporosis. Understanding the mechanisms/effects of estrogen deficiency in the presence of T1D on bone health is essential for fracture prevention in this patient population.
绝经后雌激素缺乏与骨量快速流失、骨质疏松症以及骨折风险增加有关。1型糖尿病（T1D）以低胰岛素血症和高血糖为特征，也与骨量流失和骨折风险增加有关。随着治疗方案的改善，T1D患者的寿命延长；因此，同时患有T1D和雌激素缺乏的患者数量正在增加。关于T1D合并雌激素缺乏对骨骼生理和密度的机制影响知之甚少。为了研究这一点，对11周龄的小鼠进行卵巢切除（OVX），并通过多次低剂量链脲佐菌素注射诱导T1D。显微计算机断层扫描分析表明，T1D-OVX小鼠的小梁骨体积分数（BVF）显著降低（约82%），远大于OVX组和T1D组BVF的降低幅度（约50%）。T1D-OVX小鼠的成骨细胞标志物、数量和活性显著降低，程度大于T1D或OVX小鼠。相应地，T1D-OVX小鼠骨骼中的骨髓脂肪显著增加。骨表达分析显示，肿瘤坏死因子（TNF）-α水平在T1D-OVX小鼠中最高，与骨量流失、成骨细胞和骨细胞死亡相关。体外研究表明，雌激素缺乏和高血糖会增强对炎症信号的TNF-α表达。综上所述，T1D合并雌激素缺乏对骨炎症有重大影响，这导致骨形成受抑制和骨质疏松症。了解T1D存在时雌激素缺乏对骨骼健康的机制/影响对于预防该患者群体的骨折至关重要。
