CN117487905A - Il-33在制备治疗/检测sanfh产品中的应用 - Google Patents
Il-33在制备治疗/检测sanfh产品中的应用 Download PDFInfo
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Abstract
本发明公开一种IL‑33在制备治疗/检测SANFH产品中的应用，其能够使IL‑33作为治疗靶点筛选治疗糖皮质激素诱导的股骨头缺血性坏死的药物，为发展治疗SANFH的新药物和新材料提供前期基础。
Description
技术领域
本发明涉及生物医学的技术领域，尤其涉及IL-33在制备治疗/检测SANFH产品中的应用，SANFH是指糖皮质激素诱导的股骨头缺血性坏死。
背景技术
股骨头坏死（osteonecrosis of the femoral head，ONFH）是由不同病因引起的股骨头组织细胞（骨细胞、骨髓造血细胞和脂肪细胞）死亡引起的病理过程，临床以髋关节疼痛、功能障碍为主要症状，是一种致残率极高的骨科疑难病。在我国ONFH年新发病例约10-30万，累积需要治疗病例在800万例以上，此病给患者、家属及社会带来巨大的经济和社会负担。因此，从相关机制出发寻找预防和治疗骨坏死的手段具有重大意义。
白细胞介素33（interleukin-33，IL-33）是在2005年发现的一个多功能基因，是炎症反应和免疫偏倚的重要调节因子之一，可作为核内定位的分子发挥转录因子的作用，又可被分泌到胞外起到细胞因子的作用。IL-33是IL-1家族的新成员，受体为ST2（Interleukin 1 like receptor），研究认为，IL-33是在上皮细胞受到损伤之后释放，具有多种功能，包括刺激上皮细胞的重组和促进炎症的发生。IL-33/ST2信号通路是哮喘、特发性皮炎、COPD和慢性阻碍性肺病、慢性鼻窦炎和风湿性关节炎等疾病治疗的潜在靶点。
IL-33/ST2L信号通路在骨免疫调节中起重要作用。一方面，IL-33能激活固有免疫；另一方面，IL-33与其特异性受体ST2L结合后可以调节细胞的存活、凋亡或细胞因子的产生。在体内，IL-33及ST2L表达于破骨、成骨和骨细胞，在骨免疫调节中起重要作用。研究结果表明：IL-33作为骨保护性细胞因子，能够抑制破骨细胞生成。然而IL-33/ST2通路在糖皮质激素诱导的股骨头缺血性坏死（steroid -induced avascular osteonecrosis offemoral head，SANFH）中的作用尚不清楚。因此，需要进一步实验研究来明确IL-33/ST2通路在SANFH中的作用，为SANFH的临床预防和治疗垫定前期基础。
发明内容
为克服现有技术的缺陷，本发明要解决的技术问题是提供了一种IL-33在制备治疗糖皮质激素诱导的股骨头缺血性坏死药物中的应用，其能够使IL-33作为治疗靶点筛选治疗糖皮质激素诱导的股骨头缺血性坏死的药物，为发展治疗SANFH的新药物和新材料提供前期基础。
本发明的技术方案是：这种IL-33在制备治疗/检测SANFH产品中的应用，为IL-33作为治疗靶点在筛选治疗糖皮质激素诱导的股骨头缺血性坏死的药物中的应用。
本发明将IL-33作为治疗靶点应用在筛选治疗糖皮质激素诱导的股骨头缺血性坏死的药物中，通过建立SANFH小鼠的动物模型，运用分子生物学技术检测IL-33和ST2L受体拮抗剂干预后对SANFH小鼠骨免疫的调控作用，为发展治疗SANFH的新药物和新材料提供前期基础。
优选地，IL-33/ST2L信号通路应用在骨免疫调节中。
优选地，所述应用为检测血清IL-33和ST2L蛋白在激素性股骨头坏死中的应用。
优选地，所述应用为抑制IL-33表达的物质或拮抗IL-33的物质在制备治疗支气管糖皮质激素诱导的股骨头缺血性坏死的药物中的应用。
优选地，所述拮抗IL-33的物质为IL-33的抗体。
优选地，所述应用为在制备糖皮质激素诱导的股骨头缺血性坏死骨免疫调节的药物中的应用。
优选地，所述应用为IL-33作为检测靶点在制备糖皮质激素诱导的股骨头缺血性坏死血清辅助诊断试剂中的应用。
优选地，所述应用为检测IL-33表达量的试剂在制备糖皮质激素诱导的股骨头缺血性坏死血清辅助诊断试剂中的应用。
优选地，IL-33/ST2L在糖皮质激素诱导的股骨头缺血性坏死以及血清中的表达差异，作为糖皮质激素诱导的股骨头缺血性坏死的血清分子标志物。
优选地，所述应用为IL-33的试剂盒，其用于检测IL-33及其受体ST2L在糖皮质激素诱导的股骨头缺血性坏死以及血清中的表达差异。
附图说明
图1示出了不同CJFH分型患者组间IL-33水平的差异。
图2示出了IL-33降低SANFH小鼠血液中的抗炎因子水平。
图3示出了免疫荧光检测成骨相关蛋白表达。(a)显微镜下免疫荧光观察。(b)免疫组织化学染色结果定量分析。所有数据以均数±标准差(SD)表示(对照组:n=5;ONFH组:n=5;IL-33+ONFH组:n=5)。*代表P< 0.05, **代表P< 0.01。
图4示出了Micro CT观察小鼠股骨头内结构。(a)小鼠股骨头的CT图像。(b-e)小鼠股骨头定量CT参数分析。
具体实施方式
目前关于SANFH发生发展的病理生理机制仍不明确，骨免疫微环境紊乱在激素性SANFH的发生发展中起重要作用。免疫因素与骨坏死的发病机制有关。本研究发现免疫调节细胞在股骨头骨坏死(SANFH)发展中的潜在作用。申请人回顾性研究纳入了67名确诊为SANFH的患者和58名年龄、身高和体重匹配的健康受试者。流式细胞术检测外周血T淋巴细胞亚群和B淋巴细胞亚群的数量、百分比和比例。比较不同国际骨循环协会（ARCO）分期、中日友好医院（CJFH）分型和病因组患者T淋巴细胞和B淋巴细胞水平。SANFH患者淋巴细胞总数、CD3+T细胞、T细胞(CD3+CD8+)、B-1细胞计数、B-1细胞(CD5+CD19+)均显著高于对照组。ARCO IV期患者的T淋巴细胞百分比明显小于ARCO II和III期SANFH患者。CJFH L3型患者抑制性T淋巴细胞百分比明显小于L1和L2型患者。就不同的SANFH病因而言，过量饮酒引起的SANFH患者的淋巴细胞总数和t细胞(CD3+CD8+)明显低于特发性SANFH患者。结果初步表明免疫调节细胞，如T淋巴细胞和B淋巴细胞，在SANFH的发病机制中起重要作用。SANFH的发生发展可能与免疫系统失衡有关。请参见表1、2。
表1 SANFH患者与健康人群的外周血T淋巴细胞亚群和B淋巴细胞亚群
表2 不同ARCO分期和CJFH分型的SANFH患者外周血T淋巴细胞亚群和B淋巴细胞亚群
如图1所示，免疫系统在调控成骨-破骨偶联维持骨微环境稳态具有重要作用，免疫细胞能够通过分泌不同的细胞因子和调控分子影响成骨和破骨过程。最近发现的IL-33作为IL-1细胞因子家族成员已被证明是在骨坏死骨中特异性释放的。申请人前瞻性研究发现IL-33在股骨头坏死(SANFH)发展中的潜在作用。比较不同ARCO分期、CJFH分型和病因组间IL-33水平的差异。SANFH患者血浆IL-33水平明显高于对照组。不同ARCO分期的SANFH患者IL-33水平无显著差异。L3型CJFH患者IL-33水平明显高于L1和L2型患者。在类固醇激素诱导、酒精诱导和特发性患者之间，IL-33水平无显著差异。研究结果表明，IL-33水平直接与SANFH的发病机制及预后有关。
如图2-4所示，IL-33/ST2L信号通路在骨免疫调节中起重要作用。IL-33是 IL-1家族的新型多功能细胞因子，一方面，IL-33能激活固有免疫；另一方面，IL-33与其特异性受体ST2L结合后可以调节细胞的存活、凋亡或细胞因子的产生。在体内，IL-33及ST2L表达于破骨、成骨和骨细胞，在骨免疫调节中起重要作用。研究结果表明：IL-33作为骨保护性细胞因子，能够抑制破骨细胞生成。IL-33抑制破骨细胞生成，刺激血管形成和促进骨新生血管化的作用对SANFH的修复可能有益。然而IL-33/ST2通路在激素性SANFH中的作用尚不清楚。因此，需要进一步实验研究来明确IL-33/ST2通路在SANFH中的作用，为SANFH的临床预防和治疗垫定前期基础。本项目通过建立小鼠股骨头坏死模型组，对小鼠股骨头内IL-33进行免疫荧光定量检测发现，与对照组相比，小鼠股骨头内IL-33表达增加，Westen blot 和PCR检测小鼠股骨头内IL-33和ST2L蛋白和mRNA表达量情况，发现SANFH小鼠股骨头内IL-33和ST2L蛋白和mRNA表达较对照组增加。使用IL-33对SANFH小鼠进行干预，经过HE和Masson染色，发现IL-33干预后的SANFH小鼠股骨头内炎细胞浸润加重、骨髓水肿、纤维化加重，空骨陷窝数量增加；并且对小鼠股骨头成骨指标进行免疫组化定量分析发现，IL-33干预后的SANFH小鼠股骨头内成骨指标下降，同时进行Micro-CT扫描小鼠股骨头内骨参数情况，发现IL-33干预的SANFH小鼠骨矿化密度、骨体积分数、骨小梁数量、骨小梁厚度降低。又对小鼠血清内抗炎因子进行定量分析，发现IL-33干预的SANFH小鼠血液中的抗炎因子含量是降低的。因此得出IL-33通过其受体ST2L加重SANFH局部炎症环境，促进破骨，减少成骨，导致SANFH的进展。
以上所述，仅是本发明的较佳实施例，并非对本发明作任何形式上的限制，凡是依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属本发明技术方案的保护范围。
Claims (10)
1.IL-33在制备治疗/检测SANFH产品中的应用，其特征在于：所述应用为IL-33作为治疗靶点在筛选治疗糖皮质激素诱导的股骨头缺血性坏死的药物中的应用。
2.根据权利要求1所述的IL-33在制备治疗/检测SANFH产品中的应用，其特征在于：IL-33/ST2L信号通路应用在骨免疫调节中。
3.根据权利要求1所述的IL-33在制备治疗/检测SANFH产品中的应用，其特征在于：所述应用为检测血清IL-33和ST2L蛋白在激素性股骨头坏死中的应用。
4.根据权利要求1所述的IL-33在制备治疗/检测SANFH产品中的应用，其特征在于：所述应用为抑制IL-33表达的物质或拮抗IL-33的物质在制备治疗糖皮质激素诱导的股骨头缺血性坏死的药物中的应用。
5.根据权利要求4所述的IL-33在制备治疗/检测SANFH产品中的应用，其特征在于：所述拮抗IL-33的物质为IL-33的抗体。
6.根据权利要求1所述的IL-33在制备治疗/检测SANFH产品中的应用，其特征在于：所述应用为在制备糖皮质激素诱导的股骨头缺血性坏死骨免疫调节的药物中的应用。
7.根据权利要求1所述的IL-33在制备治疗/检测SANFH产品中的应用，其特征在于：所述应用为IL-33作为检测靶点在制备糖皮质激素诱导的股骨头缺血性坏死血清辅助诊断试剂中的应用。
8.根据权利要求1所述的IL-33在制备治疗/检测SANFH产品中的应用，其特征在于：所述应用为检测IL-33表达量的试剂在制备糖皮质激素诱导的股骨头缺血性坏死血清辅助诊断试剂中的应用。
9.根据权利要求1所述的IL-33在制备治疗/检测SANFH产品中的应用，其特征在于：IL-33/ST2L在糖皮质激素诱导的股骨头缺血性坏死以及血清中的表达差异，作为糖皮质激素诱导的股骨头缺血性坏死的血清分子标志物。
10.根据权利要求1所述的IL-33在制备治疗/检测SANFH产品中的应用，其特征在于：所述应用为IL-33的试剂盒，其用于检测IL-33及其受体ST2L在糖皮质激素诱导的股骨头缺血性坏死以及血清中的表达差异。
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