Cinaciguat in combination with insulin induces a favorable effect on implant osseointegration in type 2 diabetic rats
Cinaciguat in combination with insulin induces a favorable effect on implant osseointegration in type 2 diabetic rats
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DOI：
10.1016/j.biopha.2019.109216
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发表时间：
2019-10-01
影响因子：
7.5
通讯作者：
Xu, Xin
中科院分区：
文献类型：
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作者：
Jia, Tingting;Wang, Ya-nan;Xu, Xin
2型糖尿病（T2 DM）患者种植体的骨整合过程严重受损，失败率高，而目前胰岛素治疗存在不足，需要新的骨协同剂。西那西呱是一种新型可溶性鸟苷酸环化酶（sGC）激活剂，在糖代谢、炎症控制和骨再生中起重要作用。我们假设联合应用西那西呱和胰岛素可以逆转糖尿病患者种植体骨结合不良。为了验证这一假设，将链脲佐菌素诱导的糖尿病大鼠植入股骨中，并根据接受的不同治疗分为5组：对照组、T2 DM组、西那西呱治疗的T2 DM组（7 μ g/kg）、胰岛素治疗的T2 DM组（12 IU/kg）、西那西呱+胰岛素组合治疗的T2 DM组（分别为7 μ g/kg和12 IU/kg）。处死前定时测定大鼠体重和血糖水平，并测定血浆环磷酸鸟苷（cGMP）水平。治疗后3个月，分离股骨进行拔出试验、环境扫描电镜观察、显微CT评价及各种组织学分析。结果显示，糖尿病大鼠表现出最高的血糖水平和最低的cGMP含量，这导致最严重的结构损伤和最少的骨整合。联合治疗可使糖尿病引起的高血糖降至正常水平，使cGMP含量、蛋白激酶G Ⅱ（PKG Ⅱ）表达、磷酸二酯酶5（PDE 5）活性恢复到最高水平，并使机械强度、受损的骨微结构和骨整合得到改善。同时，单用胰岛素或西那西呱也显示了修复效果，但效果较差。我们的研究结果表明，西那西呱激活cGMP/PKG II信号通路介导了联合应用改善T2 DM条件下种植体固定的有利效果。
The osseointegration process of implant is seriously impaired in type 2 diabetes mellitus (T2DM) that causes high failure rate, and insufficiency exists in current insulin therapy, creating a demand for new bone-synergistic agent. Cinaciguat, a novel type of soluble guanylate cyclase (sGC) activator, plays a vital role in glucose metabolism, inflammation control and bone regeneration. We hypothesized that the combined application of cinaciguat and insulin could reverse poor implant osseointegration in diabetes. To test this hypothesis, streptozotocin-induced diabetic rats were placed implants in the femur, and divided into five groups: control, T2DM, cinaciguat-treated T2DM (7 mu g/kg), insulin-treated T2DM (12 IU/kg), cinaciguat plus insulin combination-treated T2DM (7 mu g/kg and 12 IU/kg respectively), according to different treatment received. The weight and glucose levels of rats were evaluated at fixed times, and plasma level of cyclic guanosine monophosphate (cGMP) was determined before euthanasia. Three months after therapy, the femurs were isolated for pull-out test, environmental scanning electron microscope observation, microscopic computerized tomography evaluation and various histology analysis. Results revealed that diabetic rats showed the highest blood glucose level and lowest cGMP content, which led to the worst structural damage and least osseointegration. Combined treatment could attenuate the diabetes induced hyperglycemia to be normal, restore the cGMP content, protein kinase G II (PKG II) expression, phosphodiesterase-5 (PDE5) activity and ameliorate the mechanical strength, the impaired bone microarchitecture and osseointegration to the highest level. Meanwhile, monotreatment (insulin or cinaciguat) also showed restorative effect, but less. Our findings demonstrated that the cGMP/PKG II signaling pathway activated by cinaciguat mediated the favorable effects of the combined application on improving implant fixation under T2DM condition.