Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, China; Department of Implantology, School of Stomatology, Shandong University, Jinan, Shandong Province, China.
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, China; Department of Pediatric Dentistry, School of Stomatology, Shandong University, Jinan, Shandong Province, China.
Biomed Pharmacother. 2019 Oct;118:109216. doi: 10.1016/j.biopha.2019.109216. Epub 2019 Jul 15.
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 μg/kg), insulin-treated T2DM (12 IU/kg), cinaciguat plus insulin combination-treated T2DM (7 μg/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.
种植体的骨整合过程在 2 型糖尿病（T2DM）中受到严重损害，导致高失败率，而目前的胰岛素治疗存在不足，这就需要新的骨协同剂。西那卡塞是一种新型可溶性鸟苷酸环化酶（sGC）激活剂，在葡萄糖代谢、炎症控制和骨再生中发挥重要作用。我们假设西那卡塞和胰岛素的联合应用可以逆转糖尿病患者种植体骨整合不良。为了验证这一假设，我们将链脲佐菌素诱导的糖尿病大鼠的股骨植入物，并根据不同的治疗方法将其分为五组：对照组、T2DM 组、西那卡塞治疗的 T2DM 组（7μg/kg）、胰岛素治疗的 T2DM 组（12IU/kg）、西那卡塞加胰岛素联合治疗的 T2DM 组（分别为 7μg/kg 和 12IU/kg）。在固定时间评估大鼠的体重和血糖水平，并在安乐死前测定血浆环鸟苷酸（cGMP）水平。治疗 3 个月后，分离股骨进行拔出试验、环境扫描电子显微镜观察、微观计算机断层扫描评估和各种组织学分析。结果表明，糖尿病大鼠的血糖水平最高，cGMP 含量最低，导致结构损伤最严重，骨整合最差。联合治疗可使糖尿病引起的高血糖恢复正常，cGMP 含量、蛋白激酶 G II（PKG II）表达、磷酸二酯酶-5（PDE5）活性恢复正常，并改善机械强度、受损的骨微观结构和骨整合恢复到最高水平。同时，单一治疗（胰岛素或西那卡塞）也有一定的恢复作用，但效果稍差。我们的研究结果表明，西那卡塞激活的 cGMP/PKG II 信号通路介导了联合应用在改善 T2DM 条件下种植体固定方面的有利作用。
