CN110393792A - Dickkopf-1蛋白在制备用于治疗X-连锁低磷血症佝偻病的药剂中的用途 - Google Patents
Dickkopf-1蛋白在制备用于治疗X-连锁低磷血症佝偻病的药剂中的用途 Download PDFInfo
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Abstract
本发明涉及Dickkopf‑1(Dkk1)蛋白在制备用于治疗X‑连锁低磷血症佝偻病的药剂中的用途，属于生物医药技术领域。本发明提供Dkk1蛋白在制备用于治疗X‑连锁低磷血症佝偻病的药剂中的用途，利用Dkk1蛋白调控骨钙素水平和骨转换标志物P1NP水平，达到治疗X‑连锁低磷血症佝偻病的效果。
Description
技术领域
本发明涉及Dickkopf-1(Dkk1)蛋白在制备用于治疗X-连锁低磷血症佝偻病的药剂中的用途，属于生物医药技术领域。
背景技术
X-连锁低磷血症佝偻病(XLH)(OMIM 307800)是一种罕见的骨科遗传性疾病，其特征是血液中磷酸盐含量低，这是因为肾脏处理磷酸盐的功能异常，导致磷酸盐损失到尿液中(磷酸盐浪费)，并导致骨骼柔软、虚弱(Rickets，佝偻病或软骨病)。X-连锁低磷血症佝偻病发病诱因是PHEX(X连锁碳酸盐调节基因)基因突变，该基因编码一种内肽酶，主要表达于成骨细胞、骨细胞、成牙本质细胞和牙骨质母细胞表面。XLH遵循以显性表达为主的x连锁传播模式，除引起骨科异常外，也引起低磷血症，患者在诊断时表现为血尿增多，继发低血磷水平、碱性磷酸酶升高、甲状旁腺激素(PTH)水平正常和低尿钙。
除此之外，XLH在儿童中常见的症状为骨骼矿化不良，头骨畸形，颅缝早闭，听力障碍，身材矮小。成年患者出现继发性骨骼矿化不良，骨骼关节疼痛。组织切片检查在骨中有大量未矿化软化骨存在，伴有β-连环蛋白(β-catenin)过高表达，从而导致在成骨前期本应减少的骨钙素含量显著增加，以及骨转换标志物P1NP水平增加异常。而在骨矿化后期，相反的，机理上应增加的骨钙素和骨转换标志物的含量并没有达到生理高度。
Dkk1(dickkopf相关蛋白1)是一种分泌的小糖基化蛋白，在胚胎发生过程中表达于肢体芽中，并在出生后继续存在于已经建立的骨骼中成骨细胞和骨细胞中。
关于X-连锁低磷血症佝偻病，目前没有有效的临床治疗手段。
发明内容
本发明的目的在于克服现有技术的不足，提供Dickkopf-1(Dkk1)蛋白在制备用于治疗X-连锁低磷血症佝偻病的药剂中的用途。利用Dickkopf-1(Dkk1)蛋白调控骨钙素水平和骨转换标志物P1NP水平，达到治疗X-连锁低磷血症佝偻病的效果。
为实现上述目的，本发明采取的技术方案为：Dickkopf-1蛋白在制备用于治疗X-连锁低磷血症佝偻病的药剂中的用途。
优选地，所述药剂用于调节骨钙素水平。
优选地，所述药剂用于调节骨转换标志物P1NP水平。
另外，本发明还提供一种用于治疗X-连锁低磷血症佝偻病的药剂，所述药剂包括Dickkopf-1蛋白。
作为上述技术方案的改进，所述药剂还包括药学上可接受的辅料。
与现有技术相比，本发明的有益效果为：本发明提供Dickkopf-1(Dkk1)蛋白在制备用于治疗X-连锁低磷血症佝偻病的药剂中的用途，利用Dickkopf-1(Dkk1)蛋白调控骨钙素水平和骨转换标志物P1NP水平，达到治疗X-连锁低磷血症佝偻病的效果。
附图说明
图1为小鼠成骨细胞经正常培养基和矿化培养基培养后被提天狼猩红染色剂染色后的效果示意图；
图2为实验第一天和第十天不同DKK1剂量对矿化培养基中OCN含量的影响示意图；
图3为实验第一天和第十天不同DKK1剂量对矿化培养基中P1NP含量的影响示意图。
具体实施方式
为更好地说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明作进一步说明。
实施例1
小鼠成骨细胞(MC3T3-E1)细胞培养和细胞外胶原沉积测量
实验方法：小鼠成骨细胞(MC3T3-E1)从语纯生物技术公司获得(语纯生物，上海)，培养在α-基本培养基(α-MEM)中，添加10％胎牛血清和1％青霉素，链霉素，在5％的二氧化碳，95％氧，37℃的环境下培养，每3-5天换取新鲜培养液，使培养液保持亚饱和状态。在准备矿化实验时,用细胞计数仪计数细胞，然后将20000个细胞加入到24孔培养板的每一个孔中，培养至80％饱和度。然后在培养基加入5mMβ-glycerophosphate和100μg/ml抗坏血酸(称为矿化培养基)，每3天换液一次。为了证明细胞具有分泌细胞外基质矿化的能力，培养14天时将正常培养基(普通培养基)和矿化培养基中培养的细胞用提天狼猩红染色剂染色，用以证明基质的形成。
实验结果：图1显示，通过细胞外I-型胶原蛋白基质沉积实验，在矿化培养基中培养14天后，小鼠成骨细胞(MC3T3-E1)能够分泌I-型胶原形成细胞外基质。矿化培养基处理的细胞与普通培养基培养的细胞相比，经用提天狼猩红染色剂染色后，其颜色更深，胶原含量明显增加，由此表明本实施例的小鼠成骨细胞(MC3T3-E1)保持成骨特性，能够形成基质，最终形成新骨。
实施例2
实验方法：Dkk1蛋白购自美国R&D生物系统公司。将实施例1培养的细胞分为四组：第一组为普通培养基培养细胞，不填加任何试剂；第二组为矿化培养基对照，添加0.2μg/ml、0.4μg/ml和0.8μg/ml剂量的生理盐水；第三组为实验第一天，在矿化培养基中分别加入0.2μg/ml、0.4μg/ml和0.8μg/ml剂量的Dkk1；第四组为实验第十天，在矿化培养基中分别加入0.2μg/ml、0.4μg/ml和0.8μg/ml剂量的Dkk1。实验第十四天收集进行实验的培养基，将培养后的细胞也收集于TRIzol试剂中保存备用。采用ELISA试剂盒检测小鼠P1NP(前胶原I-型n末端前肽，Elabscience，中国)和小鼠OCN(骨钙素，Elabscience，中国)水平，实验结果如图2和图3。
实验结果：Dkk1对成骨细胞培养中骨形成生物标志物的时间效应:图2显示，不同剂量的Dkk1给药可调节细胞外OCN(骨钙素)水平，第二组矿化培养基对照处理，添加0.2μg/ml、0.4μg/ml和0.8μg/ml剂量的生理盐水，对应的OCN(骨钙素)含量分别为10.31±0.24ng/ml，9.85±0.26ng/ml，9.95±0.19ng/ml；第三组为实验第一天，在矿化培养基中分别加入0.2μg/ml、0.4μg/ml和0.8μg/ml剂量的Dkk1，对应的OCN(骨钙素)含量分别为10.95±0.87ng/ml、8.32±0.24ng/ml、7.61±0.71ng/ml，p<0.01；第四组为实验第十天，在矿化培养基中分别加入0.2μg/ml、0.4μg/ml和0.8μg/ml剂量的Dkk1，对应的OCN(骨钙素)含量分别为14.17±2.33ng/ml，14.44±0.34ng/ml，14.80±1.01ng/ml，p<0.01。由第二组、第三组和第四组对比可知，第二组对照处理，OCN(骨钙素)含量处于正常变化，而第三组相比第二组，OCN(骨钙素)含量显著降低且为剂量依赖性下降，而第四组相比第二组和第三组，OCN(骨钙素)含量显著增加且为剂量依赖性增加，由此可知，不同剂量的Dkk1给药可调节细胞外OCN(骨钙素)水平，以实现OCN(骨钙素)在患者体内拥有正常的含量，从而达到治疗X-连锁低磷血症佝偻病的效果。
DKK1对P1NP生物标志物的时间影响:收集的培养基也用ELISA法进行了P1NP检测。图3显示，不同剂量的Dkk1给药可调节P1NP水平，第二组矿化培养基对照处理，添加0.2μg/ml、0.4μg/ml和0.8μg/ml剂量的生理盐水，对应的P1NP含量分别2071.50±39.38pg/ml，1928.17±40.94pg/ml，1960.65±30.54pg/ml；第三组为实验第一天，在矿化培养基中分别加入0.2μg/ml、0.4μg/ml和0.8μg/ml剂量的Dkk1，对应的P1NP含量分别为1958.17±85.05pg/ml，1717.33±62.68pg/ml，1401.50±44.89pg/ml，p<0.001；第四组为实验第十天，在矿化培养基中分别加入0.2μg/ml、0.4μg/ml和0.8μg/ml剂量的Dkk1，对应的P1NP含量分别为2672.33±83.61pg/ml，2726.50±127.74pg/ml，2873.17±215.11pg/ml，p<0.001。由第二组、第三组和第四组对比可知，第二组对照处理，P1NP含量处于正常变化，而第三组相比第二组，P1NP含量显著降低且为剂量依赖性下降，而第四组相比第二组和第三组，P1NP含量显著增加且为剂量依赖性增加，由此可知，不同剂量的Dkk1给药可调节细胞外P1NP水平，以实现P1NP在患者体内拥有正常的含量，从而达到治疗X-连锁低磷血症佝偻病的效果。
综上，实验结果表明，在成骨细胞中添加Dickkopf-1(Dkk1)蛋白，可有效地调节骨钙素含量和骨转换标志物。在此基础上，还证明骨矿化的复杂性及这两项指标的密切可调性。从病人病理分析中发现的对其失控调节，通过Dickkopf-1(Dkk1)蛋白的给药处理而逆转，有效地达到对X-连锁低磷血症佝偻病的治疗效果。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (5)
1.Dickkopf-1蛋白在制备用于治疗X-连锁低磷血症佝偻病的药剂中的用途。
2.如权利要求1所述的用途，其特征在于，所述药剂用于调节骨钙素水平。
3.如权利要求1所述的用途，其特征在于，所述药剂用于调节骨转换标志物P1NP水平。
4.一种用于治疗X-连锁低磷血症佝偻病的药剂，其特征在于，所述药剂包括Dickkopf-1蛋白。
5.如权利要求4所述的药剂，其特征在于，所述药剂还包括药学上可接受的辅料。
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