血管性认知障碍伴骨质疏松症与Klotho/成纤维细胞生长因子23轴的关系研究进展

A review on the relationship between vascular cognitive impairment with osteoporosis and Klotho/FGF23 axis

近年来众多研究提示血管性认知障碍(Vascular Cognitive Impairment,VCI)与骨质疏松症(Osteoporosis,OP)密切相关。VCI者并发OP的走失及跌倒风险高,骨折率高,护理费用高,死亡风险高。VIC伴OP在危害国民健康的同时,也引发广泛的关注。VIC伴OP是跌倒、骨折及死亡的重要危险因素,除积极对症对因治疗外,还需尽可能找到共同风险及靶向指标积极进行综合治疗及提前干预。成纤维细胞生长因子23(Fibroblast Growth Factor 23,FGF23)/Klotho轴不仅可以调节血磷代谢,还可调控1,25二羟基维生素D3[1,25(OH)2D3]的代谢和表达。海马区损伤是导致认知障碍的主要原因之一,氧化应激反应会抑制海马神经的传导及代谢,导致学习、记忆等功能受损。故抑制氧化应激反应减轻神经炎症即可改善行为缺陷。Klotho作为一种激素蛋白,可抑制氧化应激反应从而改善认知功能。分泌型Klotho蛋白可抑制促钙化信号通路,降低TSC2磷酸化,促进Rheb酶活化,最终激活雷帕霉素靶蛋白(Mechanistic Target of Rapamycin Kinase,m TOR),调控锌离子和磷的代谢,还可调控自噬抑制血管钙化,从而改善衰老、防治认知障碍。慢性肾脏病患者,出现磷钙代谢紊乱,1α-羟化酶基因(CYP27B1)在近端肾小管的表达降低,血钙及1,25(OH)2D3下降,FGF23、血磷、甲状旁腺激素升高,出现继发性甲状旁腺功能亢进症,进而发生骨质疏松。FGF23与其受体FGFR及α-Klotho的结合激活FGF23信号转导,调节磷酸盐的肾脏排泄(磷酸尿效应)和维生素D代谢,改善骨代谢,从而缓解骨质疏松。故Klotho缺乏或FGF23增加极可能是VIC伴OP的致病机制之一。文章对VIC伴OP与Klotho/FGF23轴的关系的研究进展进行综述,希望能为VIC伴OP的研究带来新思路。

In recent years,many studies have suggested that vascular cognitive impairment is closely related to osteoporosis.Patients with vascular cognitive impairment complicated with osteoporosis have a high risk of loss and fall,a high fracture rate,high nursing costs,and a high risk of death.Vascular cognitive impairment combined with osteoporosis has caused widespread concern while endangering national health.VIC with OP is an important risk factor for falls,fractures and death.In addition to active symptomatic treatment,comprehensive treatment and early intervention should be actively conducted to find common risks and targeted indicators as much as possible.The FGF23/Klotho axis not only regulates the metabolism of blood phosphorus,but also the metabolism and expression of 1,25(OH)2D3.Hippocampal damage is one of the main causes of cognitive impairment.Oxidative stress can inhibit the conduction and metabolism of hippocampal nerve,leading to the impairment of learning,memory and other functions.Therefore,inhibiting oxidative stress and reducing neuroinflammation can improve behavioral deficits.Klotho is a hormone protein that inhibits oxidative stress and improves cognitive function.Secreted Klotho protein can inhibit the pro-calcification signaling pathway,reduce the phosphorylation of TSC2,promote the activation of Rheb enzyme,and finally activate mTOR,regulate the metabolism of Zn2+and phosphorus,and regulate autophagy to inhibit vascular calcification,so as to ameliorate aging and prevent cognitive impairment.In patients with chronic kidney disease,the metabolism of phosphorus and calcium is disturbed,the expression of CYP27B1 in the proximal renal tubules is decreased,the blood calcium and 1,25(OH)2D3 are decreased,and FGF23,blood phosphorus and iPTH are increased,resulting in secondary hyperparathyroidism,and then osteoporosis.Binding of FGF23 to its receptors FGFR andα-Klotho activates FGF23 signal transduction,which regulates renal excretion of phosphate(phosphouria effect)and vitamin D metabolism,improving bone metabolism and thereby alleviating osteoporosis.Therefore,the lack of Klotho or the increase of FGF23 may be one of the pathogenic mechanisms of VIC with OP.This article reviews the research progress on the relationship between Klotho/FGF23 axis in vascular cognitive impairment and osteoporosis,with a prospect of bringing new ideas for the research of vascular cognitive impairment with osteoporosis.