CN117883437A - Rev-erbα激动剂在制备治疗软骨疾病的药物中的应用 - Google Patents
Rev-erbα激动剂在制备治疗软骨疾病的药物中的应用 Download PDFInfo
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Abstract
本发明属于生物医学领域,具体涉及Rev‑erbα激动剂在制备治疗软骨疾病的药物中的应用。本发明中,Rev‑erbα激动剂包括GSK4112,本发明实验表明,Rev‑erbα激动剂GSK4112具有促进软骨增殖和软骨合成代谢,及抑制软骨分解代谢能力,能够促进软骨细胞增殖及其合成代谢因子Col2a1和Acan,抑制软骨细胞分解代谢Mmp13和Adamts5的表达。Rev‑erbα激动剂GSK4112能够促进小鼠跖骨生长板软骨的生长,具有良好的促进软骨再生能力,有望成为有效促进软骨再生的新药物GSK4112具有促进软骨再生的潜能,为软骨缺损修复与再生提供新的治疗策略。
Description
技术领域
本发明涉及医疗领域,尤其涉及Rev-erbα激动剂在制备治疗软骨疾病的药物中的应用。
背景技术
关节软骨是透明软骨,含有少量的细胞、胶原性的胞外基质,较多的蛋白聚糖和水。关节软骨表面光滑,能减少相邻两骨的摩擦,缓冲运动时产生的震动,因此关节软骨在关节活动中起重要作用。骨骼中存在血管或神经网络,具有自身修复能力,因此即使骨折时,骨折部分大多可以充分修复。但是,关节软骨中不存在血管和神经网络,因此几乎没有自身修复能力。由创伤、肿瘤、感染、先天性畸形、退行性疾病引起的软骨缺损严重影响患者生活质量。若是形成软骨损伤,则可能导致关节痛以及关节功能的丧失,常进展为骨关节炎。另外,由于老龄或关节的过度使用,病状由关节软骨表面开始磨损的骨关节炎的初期阶段逐步进展,结果导致大范围的软骨缺损。所以如何修复软骨损伤是临床一大难点。由于关节软骨的自身修复能力不足,目前一般采用自体骨软骨镶嵌移植术、用钻打孔的方法、钻孔术、用棒削除软骨下骨的方法、以及切除损伤软骨等治疗软骨损伤的外科处置。其中,微骨折术、钻孔术、磨削术被称为骨髓刺激法,促进骨髓出血,诱导来自骨髓的软骨前体细胞,期待其分化成软骨。但是,它们对于大范围的软骨缺损是有极限的,且通过该方法再生的是与透明软骨力学特性不同的纤维软骨。自体软骨细胞移植法是由自身的正常软骨中采集组织并培养、在将培养的细胞悬浮于培养基中的状态下移植到患部、用骨膜覆盖软骨缺损部位、使细胞不漏出的方法,但是该方法也并未显示显著优异的结果。
Rev-erbα,孤儿核受体,又称NR1D1(Nuclearreceptor subfamily 1,group D,member1),是一种广泛性表达蛋白,在脑、心脏、肝脏、肾脏、骨骼肌等脏器含量丰富,是生物钟至关重要的组件,在维持昼夜节律方面起这种重要的作用。。它本身既是生物钟基因,又是钟控基因,其表达具有明显的生物钟节律。目前研究表明,Rev-erbα具有广泛的生理调控作用,在脂肪、骨骼肌和心血管等多种器官中节律性表达并且在其器官的生物节律和细胞代谢中发挥重要作用,同时也参与调节免疫、炎症性疾病和癌症等疾病的发生发展。但是Rev-erbα激动剂在软骨疾病中是否起作用是未知的。
发明内容
本发明提供了Rev-erbα激动剂的一种新用途,具体提供了Rev-erbα激动剂在制备治疗软骨疾病的药物中的应用,为软骨疾病的治疗提供新的思路。
本发明采用以下技术方案进行。
本发明提供了Rev-erbα激动剂在制备治疗软骨疾病的药物中的应用。
本发明的一些实施方式中,所述Rev-erbα激动剂包括GSK4112。
GSK4112是一种rev-erbα(孤儿核受体NR1D1)激动剂,是第一种能够以相位依赖的方式重置生物钟的药剂。Rev-erbβ通过在核受体共抑制因子复合物(NCoR)和HDAC3的帮助下抑制靶基因活性来影响生物钟的精确度。GSK4112与血红素(rev-erβ的天然配体)竞争并增强共抑制因子复合物的募集,从而抑制转录。表明通过Rev-erα的药理学调节可以提供治疗代谢疾病的新途径,尤其是由rev-erbα调节的脂肪生成障碍。在本发明中研究GSK4112对促进软骨再生中的影响。
本发明的一些实施方式中,所述疾病包括软骨发育不良、软骨损伤和软骨退化。
本发明的一些实施方式中,所述药物用于促进软骨细胞增殖。
本发明的一些实施方式中,所述药物用于促进软骨细胞合成代谢。
本发明的一些具体实施方式中,所述药物用于促进合成代谢物Col2a1、Acan的表达。
本发明的一些实施方式中,所述药物用于抑制软骨细胞分解代谢。
本发明的一些实施方式中,所述药物用于抑制分解代谢标志物Mmp13、Adamts5的表达。
本发明第二方面提供一种治疗软骨疾病的药物,所述药物包含所述的Rev-erbα激动剂。
本发明的一些实施方式中,所述药物中Rev-erbα激动剂为单一有效成分或有效成分之一。
本发明的一些实施方式中,所述药物中Rev-erbα激动剂的含量为1w%-99w%。
本发明的一些实施方式中,所述药物中还包含药学上可接受的辅料。
本发明中,其他药学上可接受的辅料宽泛地指除活性治疗成分外的任何组分。辅料可以是惰性物质、无活性物质和/或非医药活性物质。辅料可用于各种目的,例如作为载体、媒介物、稀释剂、片剂助剂和/或用来改善活性物质的给药和/或吸收。
本发明的一些实施方式中,所述辅料选自溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂和释放阻滞剂中的一种或多种。
本发明的一些实施方式中,所述的填充剂选自淀粉、蔗糖、乳糖或微晶纤维素;所述的粘合剂选自纤维素衍生物、藻酸盐、明胶或聚乙烯吡咯烷酮;所述的润湿剂选自水、甘油、乙醇、甲基纤维素、羧甲基纤维素钠、低取代羟丙基纤维素或羟丙基甲基纤维素;所述的崩解剂选自羧甲基淀粉钠、羟丙纤维素、交联羧甲基纤维素、琼脂、碳酸钙或碳酸氢钠;所述的吸收促进剂是季铵化合物;所述的表面活性剂选自十六烷醇或十二烷基硫酸钠;所述的吸附载体选自高龄土或皂粘土;所述的润滑剂选自滑石粉、硬脂酸钙和镁、微粉硅胶或聚乙二醇;所述的矫味剂选自蔗糖、单糖浆、芳香糖浆、甘油、山梨醇或甘露醇。
与现有技术相比,本发明具有以下有益效果:本发明揭示了GSK4112具有促进软骨增殖和软骨合成代谢,及抑制软骨分解代谢能力,具有良好的促进软骨再生能力,有望成为有效促进软骨再生的新药物,为GSK4112提供了一种新的用途。
本发明中,使用Rev-erbα激动剂GSK4112处理来自乳鼠肋软骨的原代软骨细胞和乳鼠的跖骨,对其剂型细胞增殖评价和软骨细胞合成代谢及分解代谢标志物检测,结果发现,GSK4112处理后能够促进软骨细胞增殖及其合成代谢因子Col2a1和Acan的表达,抑制软骨细胞分解代谢Mmp13和Adamts5的表达。经GSK4112处理后,其细胞增值率最高提高了24.55%。因此,Rev-erbα激动剂GSK4112能够促进小鼠跖骨生长板软骨的生长,具有良好的促进软骨再生能力,有望成为有效促进软骨再生的新药物GSK4112具有促进软骨再生的潜能,为软骨缺损修复与再生提供新的治疗策略。
附图说明
图1为不同浓度GSK4112对原代软骨细胞增殖的影响。
图2为不同浓度GSK4112对跖骨累积生长长度和累积生长率;其中,图2的A表示不同浓度GSK4112对跖骨累积生长长度的影响;图2的B表示不同浓度GSK4112对跖骨累积生长率的影响柱状图。
图3为GSK4112对跖骨生长板静息区(EZ)、增殖区(PZ)和肥大区(HZ)高度的影响;其中,图3的A为跖骨生长板静息区(EZ)、增殖区(PZ)和肥大区(HZ)高度对照图;图3的B为跖骨生长板静息区(EZ)、增殖区(PZ)和肥大区(HZ)高度柱状图。
图4为GSK4112对跖骨生长板软骨增殖的影响。
图5为GSK4112对跖骨生长板软骨细胞合成代谢及分解代谢的影响;其中,图5的A为合成代谢标志物Col2a1的表达水平;图5的B为合成代谢标志物Acan的表达水平;图5的C为分解代谢标志物Mmp13的表达水平;图5的D为分解代谢标志物Adamts5的表达水平。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明,但不应理解为本发明的限制。如未特殊说明,下述实施例中所用的技术手段为本领域技术人员所熟知的常规手段,下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
本发明实施例中,GSK4112采用美国Selleck公司生产,货号:S5182。
实施例1:Rev-erbα激动剂GSK4112在促进软骨再生的应用
1、细胞水平评估细胞增殖能力
所使用的原代软骨细胞来源于0-3天龄的C57/BL6乳鼠肋软骨,具体实施方法如下:将乳鼠断头处死后在75酒精中浸泡3分钟左右消毒处理,转移到无菌操作台内,分离出肋软骨置于无菌PBS中,洗2遍,转移至含0.2%胶原酶(Sigma,C5138)培养皿中,培养箱中消化1h。移除胶原酶后,加入PBS吹打肋软骨去除肋软骨周围的结蹄组织,带结蹄组织完全脱落后将肋软骨转移至新的0.2%胶原酶培养皿中,培养箱中消化2h,加入完全培养基(F12+10%FBS+1%青霉素/链霉素)终止消化,不断吹打肋软骨,直至软骨细胞完全散开,用无菌细胞滤膜过滤细胞,2000rpm,离心5min,用完全培养基重悬培养。
细胞增殖评估:待原代软骨细胞融合80%后,将软骨细胞铺至96孔板中(每孔3000个细胞),培养12h后,将不同浓度的GSK4112(0、5、10、20、40、80、160、320μM)干预软骨细胞24小时,使用CCK-8试剂盒(碧云天,C0038)进行评估软骨细胞增殖情况。
结果如图1所示,5μM、10μM、20μM GSK4112具有明显的促进软骨细胞增殖能力(相对于不添加GSK4112增殖率分别提高了:9.28%、24.55%、26.95%)。
2、GSK4112促进软骨再生试验
(1)本试验使用0天出生的C57/BL6小鼠的第2、3、4跖骨体外培养。具体提取方法:将乳鼠断头处死后在75酒精中浸泡3分钟左右消毒处理,转移到无菌操作台内,显微镜下分离出第2、3、4跖骨,置于跖骨培养基中(α-MEM+0.05mg/mL维生素C(1043003,Merck),1mM甘油磷酸钠(G9422,Merck)+0.2%BSA+1%青霉素/链霉素),培养于CO2细胞培养箱中,培养12h后记录跖骨的长度,作为第0天初始长度L0,将不同浓度的GSK4112加入跖骨中(0、2.5、5、10、20、40uM),培养3天,分别记录第3天跖骨的长度L3,计算跖骨累积生长长度(L3-L0)和累积生长率(L3-L0)/L0。
结果如图2所示:10μM、20μM、40μM、80μM GSK4112组累积生长长度和累积生长率明显高于0μM组。以下所有实验选择10μM GSK4112作为治疗浓度。
(2)甲苯胺蓝染色:将培养3天后的跖骨固定于多聚甲醛中48小时后,石蜡包埋、切片、甲苯胺蓝染色。具体如下:
1)脱水包埋:将跖骨组织置于包埋盒中,自来水冲洗8h,按照以下步骤。80%乙醇20min、90%乙醇20min、100%乙醇I 20min、100%乙醇II-20min、二甲苯+100%乙醇(1:1)10min、二甲苯II 10min、二甲苯II 10min、二甲苯+石蜡(1:1)10min、石蜡I1h、石蜡II 1h,进行乙醇梯度脱水及石蜡包埋。
将已包埋的组织蜡块切成4μm厚的切片备用。
2)甲苯胺蓝染色
(a)脱蜡:二甲苯中浸泡8min。
(b)水化:将组织切片依次置于100%、95%、85%、75%乙醇、纯水中梯度水化各2min。
(c)甲苯胺蓝染色:将甲苯胺蓝溶液滴加到组织切片上,常温孵育2min后,自来水冲洗切片。
(d)脱水:将组织切片置于95%乙醇中脱水2min,然后置于100%乙醇中直至骨组织的红色完全褪去只有软骨为红色为止。
(e)透明:置于二甲苯中透明3min。
(f)封片:将组织上滴加中性树胶封片,镜下拍照。
3)测量生长板静息区、增殖区及肥大区高度。
结果如图3所示,GSK4112跖骨生长板增殖区明显高于Control组。
3、增殖实验评估:跖骨培养3天,加入Brdu(00-0103,Invitrogen)至24孔板中,培养4h后收集跖骨于多聚甲醛中固定,按照方法2进行石蜡包埋、切片。免疫组化法检测Brdu表达水平。
结果如图4所示,GSK4112跖骨生长板增殖区Brdu表达水平明显高于control组,说明GSK4112具有促进软骨细胞增殖的能力。
4、软骨细胞合成代谢及分解代谢标志物检测
为证实GSK4112对软骨细胞合成代谢及分解代谢影响,进一步提取跖骨mRNA,使用RT-PCR检测合成代谢标志物(Col2a1、Acan)及分解代谢标志物(Mmp13、Adamts5)
结果如图5所示,GSK4112组软骨合成代谢标志物Col2a1、Acan明显高于0μM组;而分解代谢标志物(Mmp13、Adamts5)明显低于control组。因此,说明GSK4112可以促进软骨合成。
尽管已描述了本发明的优选实施例,但本领域内的技术人员一旦得知了基本创造性概念,则可对这些实施例作出另外的变更和修改。所以,所附权利要求意欲解释为包括优选实施例以及落入本发明范围的所有变更和修改。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (10)
1.Rev-erbα激动剂在制备治疗软骨疾病的药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述Rev-erbα激动剂包括GSK4112。
3.如权利要求1所述的应用,其特征在于,所述疾病包括软骨发育不良、软骨损伤和软骨退化。
4.如权利要求1所述的应用,其特征在于,所述药物用于促进软骨细胞增殖。
5.如权利要求1所述的应用,其特征在于,所述药物用于促进软骨细胞合成代谢。
6.如权利要求1所述的应用,其特征在于,所述药物用于抑制软骨细胞分解代谢。
7.一种治疗软骨疾病的药物,其特征在于,所述药物包含权利要求1中所述的Rev-erbα激动剂。
8.如权利要求7所述的药物,其特征在于,所述药物中Rev-erbα激动剂为单一有效成分或有效成分之一。
9.如权利要求7所述的药物,其特征在于,所述药物中Rev-erbα激动剂的含量为1w%-99w%。
10.如权利要求7所述的药物,其特征在于,所述药物中还包含药学上可接受的辅料。
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