CN117731758A - 一种包括hapln1作为有效成分的用于软骨再生的组合物 - Google Patents
一种包括hapln1作为有效成分的用于软骨再生的组合物 Download PDFInfo
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- CN117731758A CN117731758A CN202311567985.1A CN202311567985A CN117731758A CN 117731758 A CN117731758 A CN 117731758A CN 202311567985 A CN202311567985 A CN 202311567985A CN 117731758 A CN117731758 A CN 117731758A
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Abstract
本发明涉及一种包括HAPLN1作为有效成分的用于软骨再生的组合物，根据本发明，HAPLN1蛋白具有促进软骨形成和关节软骨再生的能力，可以通过提高软骨细胞中TGF‑β受体I的表达水平来增加具有软骨形成能力的细胞的组成比并诱导软骨组织再生。因此，本发明的HAPLN1蛋白作为用于调节TGF‑β信号传导的新型组合物，可有效地用作用于软骨再生的药物组合物、用于软骨再生的保健食品组合物或用于软骨再生的试料组合物。
Description
本申请是国际申请日为2018年8月29日、国际申请号为PCT/KR2018/009996于2020年2月28日进入中国国家阶段、申请号201880056630.7、发明名称“一种包括HAPLN1作为有效成分的用于软骨再生的组合物”的申请的分案申请。
技术领域
本发明涉及一种包括透明质酸和蛋白聚糖连接蛋白1(hyaluronan andproteoglycan link protein 1，HAPLN1)作为有效成分的用于软骨再生的组合物。
背景技术
在人体骨骼相遇的铰链部分，由透明软骨(hyaline cartilage)组成的关节软骨
(articular cartilage)相互接触以施加内部压力和拉力，并且每个关节具有滑液囊(synovial capsule)包含滑液(synovial fluid)的形式，从而减少由关节运动引起的摩擦力。
关节软骨与生长板(growth plate)软骨一起对应于软骨的形式中透明软骨，这些软骨组织的细胞外基质(extracellular matrix，ECM)以Ⅱ型胶原蛋白(typeⅡcollagen)、蛋白聚糖(aggrecan)、透明质酸(hyaluronan)、HAPLN1(hyaluronan and proteoglycanlink protein 1)等作为主要成分具有聚集体(aggregate)结构。其中，已知多数蛋白聚糖与透明质酸链结合，并HAPLN1通过更牢固地结合其两者的键而起到在物理化学上稳定聚集体的作用。
在膝关节中软骨厚度约为2mm，当该区域因外伤或疾病而受损1mm2至4mm2时，可以通过自然愈合来再生，但当受损约20mm2时，很难通过自生能力来再生，并且通常带来极大的痛苦。另外，当由于如肿瘤和坏死等的各种原因而完全丧失关节软骨时，为了恢复关节功能，进行例如将人工关节嵌入相应位置等的治疗。然而，由于人工关节为与关节功能类似的人工构造而已，因此对生物体来说是异物，从而难以保持生物相容性。另外，由于人工关节需要在生物体内的严格环境中进行复杂的运动，因此难以维持20年以上，在某些情况下，用作其材料的树脂或金属等的劣化、磨损粉末的产生等可以导致功能降低或疼痛，并且也不能说耐久性足够。因此，作为人工关节治疗的替代，需要一种用于再生关节软骨本身的技术。
另外，根据最近的研究，已经报道了通过穿刺关节表面并将含有骨形成因子(bonemorphogenetic protein，BMP)的胶原蛋白放置在所需区域来进行的关节软骨再生。然而，再生的关节软骨不与相邻的既有关节软骨连续形成，因此这不能说是完全的再生。此外，由于牛海绵状脑病(bovine spongiform encephalopathy，BSE)，所谓疯牛病之类的问题，胶原蛋白倾向于避免在生物体内应用。因此，需要开发仅使用公认的生物应用材料来再生软骨的新型组合物。
发明内容
技术问题
本发明的一目的在于提供一种用于软骨再生的药物组合物。
本发明的另一目的在于提供一种用于软骨再生的保健食品组合物。
本发明的另一目的还在于提供一种用于软骨再生的试料组合物。
本发明的另一目的还在于提供一种在体外(in vitro)再生软骨组织的方法。
技术方案
为了实现所述目的，本发明提供一种包括透明质酸和蛋白聚糖连接蛋白1
(hyaluronan and proteoglycan link protein 1，HAPLN1)作为有效成分的用于软骨再生的药物组合物、用于软骨再生的保健食品组合物或用于软骨再生的试料组合物。
另外，本发明提供一种通过处理透明质酸和蛋白聚糖连接蛋白1(hyaluronan andproteoglycan link protein 1，HAPLN1)来在体外(in vitro)再生软骨组织的方法。
有益效果
根据本发明，HAPLN1蛋白具有促进软骨形成和关节软骨再生的能力，可以通过提高软骨细胞中TGF-β受体I的表达水平来增加具有软骨形成能力的细胞的组成比并诱导软骨组织再生。因此，本发明的HAPLN1蛋白作为用于调节TGF-β信号传导的新型组合物，可有效地用作用于软骨再生的药物组合物、用于软骨再生的保健食品组合物或用于软骨再生的试料组合物。
附图说明
图1为确认由于对衰老小鼠的退化的生长板反复腹膜内给予HAPLN1蛋白而引起的软骨形成能力的图，图1(A)为通过番红O/固绿FCF(Safranin O/Fast Green FCF)染色法来确认组织中蛋白聚糖的图，图1(B)为通过免疫组织化学(immunohistochemistry)来确认具有软骨形成能力的软骨细胞的存在的图。
图2为通过免疫荧光(immunofluorescence)来确认对小鼠受损膝关节组织关节腔内给予HAPLN1蛋白的软骨再生能力的图。
图3为确认HAPLN1蛋白在人类关节软骨细胞促进软骨形成的能力的图，图3(A)为通过聚合酶链反应(polymerase chain reaction，PCR)来确认软骨特异性基因SOX9、软骨底物成分蛋白聚糖和Ⅱ型胶原蛋白的基因表达量的图，图3(B)为通过番红O/固绿FCF染色法来确认在细胞外基质积聚的蛋白聚糖的图。
图4为确认HAPLN1蛋白在小鼠关节软骨细胞中的TGF-β信号传导调节能力的图，图4(A)为通过免疫印迹法(western blot)来确认HAPLN1蛋白的TGF-β受体I调节能力的图，图4(B)和4(C)为通过聚合酶链反应和免疫印迹法来确认HAPLN1蛋白的TGF-β受体I稳定能力的图，图4(D)为通过免疫印迹法来确认由HAPLN1蛋白进行的细胞表面TGF-β受体I呈递能力的图。
具体实施方式
本发明的发明人已经确认在衰老的小鼠和关节软骨损伤的小鼠中由HAPLN1蛋白进行的促进软骨形成和软骨再生的能力。另外，由HAPLN1蛋白进行的促进软骨形成能力在软骨细胞中也有效，并且通过增加软骨细胞的TGF-β受体I的给予量来确认信号调节效果，从而完成了本发明。
本发明提供一种包括透明质酸和蛋白聚糖连接蛋白1(hyaluronan andproteoglycan link protein 1，HAPLN1)作为有效成分的用于软骨再生的药物组合物。
优选地，所述HAPLN1可以促进软骨形成并保护关节软骨。
优选地，所述HAPLN1可以提高TGF-β受体I的表达水平，以增加具有软骨形成能力的细胞的组成比并诱导软骨组织再生。
当本发明的组合物为药物组合物时，为了给药，除上述有效成分外，还可以包括药学上可接受的载体、赋形剂或稀释剂。所述载体、赋形剂和稀释剂可以包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶细胞纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯(methyl hydroxybenzoate)、羟基苯甲酸丙酯(propyl hydroxybenzoate)、滑石粉、硬脂酸镁和矿物油。
根据常规方法，本发明的药物组合物可以分别制成粉剂、颗粒剂、片剂、胶囊剂、混悬剂、乳剂、糖浆剂、气雾剂等的口服剂型、外用剂、栓剂或无菌注射溶液的形式以使用。具体地，当配制时，可以通过使用稀释剂或赋形剂如常用的填充剂、增重剂、粘合剂、湿润剂、崩解剂、表面活性剂等来制备。用于口服的固体制剂包括但不限于片剂、丸剂、散剂、颗粒剂、胶囊剂等。这种固体制剂可以通过混合除所述有效成分外的至少一种赋形剂如淀粉、碳酸钙、蔗糖、乳糖、明胶等来制备。另外，除了简单的赋形剂之外，还可以使用如硬脂酸镁、滑石等的润滑剂。除了用于口服的液态物、液体石蜡以外，还可以通过添加各种赋形剂，例如润湿剂、甜味剂、芳香剂、保存剂等来制备。用于非口服给药的制剂可以包括无菌水溶液、非水性溶剂、混悬溶剂、乳剂、冻结干燥剂和栓剂等。非水性溶剂和混悬溶剂可以使用丙二醇、聚乙二醇、植物油如橄榄油、可注射的酯如乙醇酸酯等。作为栓剂的基质，可以使用Witepsol、Macrogol、吐温61、可可油脂、月桂精油、甘油明胶等。
本发明药物组合物的合适的给药量，可根据患者的状况和体重、疾病的程度、药物形态、时间而不同，但本领域技术人员可以适当地选择，所述组合物的每日给药量优选为0.001mg/kg至50mg/kg，可根据需要每天给药一次至几次。
另外，本发明提供一种包括透明质酸和蛋白聚糖连接蛋白1(hyaluronan andproteoglycan link protein 1，HAPLN1)作为有效成分的用于软骨再生的保健食品组合物。
当本发明的组合物为保健食品组合物时，可以包括各种营养剂、维生素、矿物质(电解质)、合成调味剂和天然调味剂等调味剂、着色剂和增味剂(奶酪、巧克力等)、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、酒精、碳酸饮料中使用的碳酸化剂等。其他可以包括用于生产天然果汁、合成果汁和蔬菜饮料的果肉。所述组分可以单独或组合使用。另外，所述保健食品组合物可以为肉类、香肠、面包、巧克力、糖果类、零食类、饼干类、比萨、拉面、口香糖类、冰淇淋类、汤、饮料、茶、功能水、饮料剂、酒精和维生素复合剂中的任何一种形式。
另外，所述保健食品组合物可以进一步包括食品添加剂，并且除非另有规定，根据食品医药品安全处批准的《食品添加物公典》的总则和通用试验法等，作为食品添加剂的适用性应当按照有关该项目的规格和标准确定。
所述收载于《食品添加物公典》的项目例如为诸如酮类、甘氨酸、柠檬酸钾、烟酸、肉桂酸等的化学合成品，诸如柿子色素、甘草提取物、结晶纤维素、高梁色素、瓜儿胶等的天然添加物，诸如L-谷氨酸钠制剂、面类添加碱剂、保存剂、焦油色素制剂等的混合制剂类等。
此时，可以根据需要适当地添加或减少在制备保健食品组合物的过程中添加于食品的根据本发明的组合物的含量。
另外，本发明提供一种包括透明质酸和蛋白聚糖连接蛋白1(hyaluronan andproteoglycan link protein 1，HAPLN1)作为有效成分的用于软骨再生的试料组合物。
另外，本发明提供一种通过处理透明质酸和蛋白聚糖连接蛋白1(hyaluronan andproteoglycan link protein 1，HAPLN1)来在体外(in vitro)再生软骨组织的方法。
以下将参考实施例更详细地描述本发明。这些实施例仅用于更具体地描述本发明，对于本领域普通技术人员将显而易见的是，根据本发明要旨，本发明的范围不受这些实施例的限制。
实施例1：分析在体内(in vivo)退化的软骨组织中由HAPLN1蛋白进行的软骨再生能力。
1-1、通过反复腹膜内给予HAPLN1蛋白来促进退化的生长板中软骨形成。
将6周龄的雄性C57BL/6小鼠分类为年轻(Young)组，将20月龄的C57BL/6小鼠分类为老化(Old)组。在老化组中，将HAPLN1蛋白稀释于磷酸盐缓冲盐水(phosphate bufferedsaline，PBS)并每天以0.1mg/kg的剂量腹膜内给药两周；在对照组中，以相同方式腹膜内给药PBS。
取每组的小鼠股骨和膝关节部位并用中性缓冲10％福尔马林(neutral buffered10％formalin，NBF)固定48小时，然后用10％乙二胺四乙酸(ethylenediaminetetraaceticacid，EDTA)溶液连续进行脱矿过程7天。随后，将每个受试体包埋(embedding)在石蜡(paraffin)中以制备石蜡块，并且在矢状方向上制备5μm厚的组织切片玻片。为了进行组织学评估，将每个组织切片玻片的软骨组织通过进行番红O/固绿FCF(safranin O/fastgreen FCF，SO/FG)染色法来可视化。通过使用Ni-U(Nikon)显微镜和DS-Ri1(Nikon)数码相机拍摄图像来对完成染色的组织切片进行观察，其结果如图1(A)所示(比例尺＝1mm)。
如图1(A)所示，与年轻对照组(Young Control)相比，老化对照组(Old Control)的生长板退化并仅可以确认软骨组织的痕迹，而在反复腹膜内给予HAPLN1蛋白的老化组(Old HAPLN1)中，可以确认在退化的生长板上形成了软骨(箭头)。
1-2、通过反复腹膜内给予HAPLN1蛋白来形成和增加具有软骨形成能力的软骨细
胞。
从所述实施例1-1中，为了确认在通过反复腹膜内给予HAPLN1蛋白来诱导的软骨形成部位是否存在具有软骨形成能力的细胞，通过免疫组织化学(immunohistochemistry，IHC)对该部位的作为软骨特异性转录因子的SOX9(cartilage-specific transcriptionfactor)进行染色。通过使用Ni-U(Nikon)显微镜和DS-Ri1(Nikon)数码相机拍摄图像来对完成染色的组织切片进行观察，其结果如图1(B)所示(比例尺＝1mm)。
如图1(B)所示，年轻对照组(Young Control)在整个软骨组织中具有表达SOX9的细胞，而在老化对照组(Old Control)中未发现表达SOX9的细胞。但是，可以确认在反复腹膜内给予HAPLN1蛋白的老年组(Old HAPLN1)的软骨形成刺激部位发现了大量表达SOX9的细胞(箭头)。
实施例2：分析在体内(in vivo)受损的软骨组织中由HAPLN1蛋白进行的软骨再生能力。
将7周龄的雄性C57BL/6小鼠分为以下三组。正常对照组(Sham Control组)为用于内侧半月板不稳定(destabilization of medial meniscus，DMM)手术的假手术组(shamoperation)，手术后在现有条件下饲养4周。在DMM手术后，将Vehicle处理组(DMM Control组)在现有条件下饲养8周，并在最后4周内每周一次关节腔内给予PBS。在DMM手术后，将HAPLN1处理组(DMM HAPLN1组)在现有条件下饲养8周，然后将HAPLN1蛋白以1μg/mL的浓度稀释于PBS并在最后4周内每周一次关节腔内给药。
当饲养结束时，摘除进行手术和治疗的膝盖组织并用NBF固定48小时，然后用10％EDTA溶液进行脱矿过程7天。随后，将每个受试体包埋在石蜡中以制备石蜡块，并且在矢状方向上制备5μm厚度的组织切片玻片。使用免疫荧光(immunofluorescence，IF)将II型胶原蛋白(type II collagen，Col2)以绿色荧光染色，并使用4',6-二脒基-2-苯基吲哚(4',6-diamidino-2-phenylindole，DAPI)将细胞的核以蓝色荧光染色。通过使用Ni-U(Nikon)显微镜和DS-Ri1(Nikon)数码相机拍摄图像来对完成染色的组织切片进行观察，其结果如图2所示(比例尺＝200mm)。
如图2所示，可以确认正常对照组(Sham Control组)中发现的Ⅱ型胶原蛋白表达细胞的数量在Vehicle处理组(DMM Control组)显着减少，而HAPLN1处理组(DMM HAPLN1组)中Ⅱ型胶原蛋白表达细胞的数量显着增加(箭头)。
实施例3：分析HAPLN1蛋白的体外(in vitro)促进软骨形成的能力。
3-1、HAPLN1蛋白增加人关节软骨细胞的软骨形成能力。
将人关节软骨细胞(human articular chondrocyte，HAC)在含有10％胎牛血清(fetal bovine serum，FBS，Gibco)、1％青霉素/链霉素(penicillin/streptomycin，Gibco)、1％非必需氨基酸(non-essential amino acid，NEAA；Gibco)的DMEM/F12(DMEM/F12，Gibco)1：1混合培养基于37℃和5％二氧化碳条件下培养。
作为用于测试HAC的软骨形成能力的模型，使用将细胞包埋在藻酸盐珠(alginatebead)中的三维培养系统。将HAC均匀混合于1.25％藻酸盐(alginate)溶液，以使每个珠子包括30,000个细胞。通过向所述生长培养基添加50μg/mL的L-抗坏血酸2-磷酸酯(L-ascorbic acid 2-phosphate)、1％胰岛素铁硒传递蛋白(insulin-transferrin-selenium，INS，Gibco)和10ng/mL的TGF-β1来进行培养，并向HAPLN1处理组进一步添加50ng/mL的HAPLN1。在37℃、5％二氧化碳的条件下继续培养7天至28天。
当培养结束时，为了回收包埋在藻酸盐珠中的HAC，将藻酸盐溶解于55mM EDTA溶液，然后以500xg进行离心分离(centrifugation)3分钟。对经离心分离后获得的细胞进行RNA提取和聚合酶链反应(polymerase chain reaction，PCR)，以比较和分析基因表达模式，其具体过程如下。
根据制造商的说明，使用TRIzol(Thermo Scientific)溶液提取RNA。使用oligo-dT20引物(primer)和SuperScriptⅢFirst-Strand Synthesis Supermix(Invitrogen)，从获得的RNA0.1μg合成第一链cDNA。通过iQ SYBR Green Supermix(Bio-rad)，用针对每个目的基因的200nM引物对获得的cDNA进行PCR。反应条件为：在最初的5分钟保持95℃之后，将95℃10秒、62℃15秒和72℃20秒的三个步骤重复45次。通过CFX Connect(Bio-rad)实时测量扩增的信号，并相对于各自甘油醛3-磷酸脱氢酶(GAPDH)表达量计算目的基因的表达量。其结果如图3(A)所示，用于PCR的每个人基因的引物序列如下。
【表1】
如图3(A)所示，可以确认HAPLN1蛋白引起HAC增加SOX9基因表达，而同时增加蛋白聚糖(aggrecan，ACAN)和Ⅱ型胶原蛋白(type II collagen，COL2A1)的基因表达。
3-2、HAPLN1蛋白增加人关节软骨细胞的胞外基质中蛋白聚糖的积累。
从所述实施例3-1中，为了评估通过添加HAPLN1而形成的软骨基质的细胞外蓄积，将培养第28天的藻酸盐微珠用NBF固定15分钟，并在OCT化合物(Sakura)中用液氮冻结。由此获得5μm厚的冻结切片，并用丙酮(acetone)固定后通过番红O/固绿FCF染色法进行可视化。通过使用Ni-U(Nikon)显微镜和DS-Ri1(Nikon)数码相机拍摄图像来对染色的组织切片进行观察，其结果如图3(B)所示(比例尺＝250μm)。
如图3(B)所示，可以确认在含有HAPLN1蛋白的培养基中培养的HAC的藻酸盐珠中，用番红O染色的蛋白聚糖的积累与其对照组相比显着增加。
实施例4：分析由HAPLN1蛋白进行的TGF-β信号传导调节能力。
4-1、HAPLN1蛋白增加小鼠关节软骨细胞中TGF-β受体I(TβR1)的蛋白质含量。
从5日龄ICR小鼠的双侧关节软骨中分离出未成熟的小鼠关节软骨细胞(immaturemurine articular chondrocyte，iMAC)。将获得的iMAC在包括10％FBS(Gibco)、1％青霉素/链霉素(penicillin/streptomycin，Gibco)、1％NEAA(Gibco)的DMEM/F12(Gibco)培养基中于37℃、5％二氧化碳的条件下培养。
在板底高密度培养的iMAC中，处理100ng/mL HAPLN1 3小时至72小时后收集细胞，并在放射免疫沉淀测定(radioimmunoprecipitation assay，RIPA)缓冲液中提取蛋白质。然后进行免疫印迹法(western blot)以确认TGF-β受体I(TβR1)、激活素受体样激酶1(activin receptor-like kinase 1，ALK1)，TGF-β受体II(TβR2)和Gapdh的蛋白表达水平，其结果如图4(A)所示。
如图4(A)所示，可以确认HAPLN1蛋白提高iMAC的TGF-β受体I(TβR1)的蛋白表达水平。另一方面，可以确认激活素受体样激酶1(activin receptor-like kinase 1，ALK1)和TGF-β受体II(TβR2)的表达水平没有改变。
4-2、HAPLN1蛋白增加小鼠关节软骨细胞中TGF-β受体I(TβR1)的稳定性。
为了验证所述实施例4-1中所示的由HAPLN1蛋白引起的TGF-β受体I(TβR1)蛋白水平的增加是稳定性增加的结果，从在相同实验条件下分别培养24小时和72小时的细胞中，比较和分析已比较蛋白质水平的三个基因的表达模式，同时验证在限制蛋白质从头合成(de novo synthesis)的环境中由HAPLN1蛋白引起的TGF-β受体I(TβR1)蛋白水平的增加。
为此的RNA提取和PCR过程如下。
根据制造商的说明，使用TRIzol(Thermo Scientific)溶液提取RNA。使用oligo-dT20引物和SuperScript III First-Strand Synthesis Supermix(Invitrogen)，从获得的RNA0.1μg合成第一链cDNA。通过iQ SYBR Green Supermix(Bio-rad)，用针对每个目的基因的200nM引物对获得的cDNA进行PCR。反应条件为：在最初的5分钟保持95℃之后，将95℃10秒、61℃15秒和72℃20秒的三个步骤重复45次。通过CFX Connect(Bio-rad)实时测量扩增的信号，并相对于各自GAPDH表达量计算目的基因的表达量。其结果如图4(A)所示，用于PCR的每个小鼠基因的引物序列如下。
【表2】
另外，在以高密度培养在平板底部的iMAC中处理和露出环己酰亚胺(cycloheximide，CHX)的过程中，在处理环己酰亚胺(CHX)0.5小时之前(pre)或0.5小时之后(post)处理200ng/mL HAPLN1。在处理环己酰亚胺(CHX)24小时后，用PBS清洗附着有细胞状态的平板，然后收集细胞以在RIPA缓冲液中提取蛋白质。用提取的细胞裂解物(celllysate)进行免疫印迹法以确认TGF-β受体I(TβR1)、激活素受体样激酶1(activinreceptor-like kinase 1，ALK1)、TGF-β受体II(TβR2)和Gapdh的蛋白表达水平，其结果如图4(C)所示。
如图4(B)和4(C)所示，可以确认iMAC的TGF-β受体I(TβR1)、激活素受体样激酶1(activin receptor-like kinase 1，ALK1)和TGF-β受体II(TβR2)均未通过HAPLN1蛋白诱导或抑制其基因表达。另一方面，可以确认与激活素受体样激酶1(activin receptor-likekinase 1，ALK1)和TGF-β受体II(TβR2)不同，HAPLN1蛋白增加TGF-β受体I(TβR1)的表达水平。这表明HAPLN1蛋白增加了TGF-β受体I(TβR1)蛋白的半衰期而没有诱导其基因的转录，这意味着iMAC拥有的TGF-β受体I(TβR1)蛋白的稳定性得到提高。
4-3、HAPLN1蛋白增加小鼠关节软骨细胞中TGF-β受体I(TβR1)的细胞表面给予量。
在以高密度培养在平板底部的iMAC中处理和露出环己酰亚胺(cycloheximide，CHX)的过程中，在处理环己酰亚胺(CHX)0.5小时之前(pre)或0.5小时之后(post)处理200ng/mL HAPLN1。在处理环己酰亚胺(CHX)24小时后，用PBS清洗附着有细胞状态的平板，然后反应Link Sulfo-NHS-LC-Biotin(Thermo Scientific)2小时以用生物素(biotin)标记细胞表面蛋白。用0.1M甘氨酸溶液终止反应后，收集细胞并在NP-40裂解缓液(Bioworld)中提取蛋白质。通过使用生物素(biotin)抗体和磁珠(magnetic bead)的免疫沉淀法来选择性地提取标记有生物素(biotin)的细胞表面蛋白，并对如此获得的馏分进行免疫印迹法以确认TGF-β受体I(TβR1)、ALK1(activin receptor-like kinase 1)、TGF-β受体II(TβR2)和Gapdh的蛋白表达水平，其结果如图4(D)所示。
如图4(D)所示，可以确认HAPLN1蛋白增加iMAC细胞表面上存在的TGF-β受体I(TβR1)蛋白的表达水平，而ALK1(activin receptor-like kinase 1)和TGF-β受体II(TβR2)的表达未改变。
下面将描述根据本发明的包括HAPLN1的组合物的制备例，但这仅仅是为了详细描述本发明，而无意于限制本发明。
<处方例1>药物组合物的处方例
<处方例1-1>粉剂的制备
通过将20mg HAPLN1、100mg乳糖和10mg滑石粉混合并装入密闭袋中来制备粉剂。<处方例1-2>片剂的制备
<处方例1-2>片剂的制备
将20mgHAPLN1、100mg玉米淀粉、100mg乳糖和2mg硬脂酸镁混合，然后按照常规的片剂制备方法进行压片以制备片剂。
<处方例1-3>胶囊剂的制备
将10mgHAPLN1、100mg玉米淀粉、100mg乳糖和2mg硬脂酸镁混合，然后按照常规的胶囊剂制备方法将所述成分混合并装入明胶胶囊中以制备胶囊剂。
<处方例1-4>注射剂的制备
将10mgHAPLN1、注射用无菌蒸馏水适当量和pH调节剂适当量混合，然后按照常规的注射剂制备方法以每安瓿(2ml)的所述成分含量进行制备。<处方例1-5>软膏剂的制备
<处方例1-5>软膏剂的制备将10mgHAPLN1、250mgPEG-4000、650mgPEG-400、10mg白凡士林、1.44mg对羟基苯甲酸甲酯、0.18mg对羟基苯甲酸丙酯和剩余量的纯净水混合，然后按照常规的软膏剂制备方法以制备软膏剂。
将10mgHAPLN1、250mgPEG-4000、650mgPEG-400、10mg白凡士林、1.44mg对羟基苯甲酸甲酯、0.18mg对羟基苯甲酸丙酯和剩余量的纯净水混合，然后按照常规的软膏剂制备方法以制备软膏剂。
<处方例2>保健食品
<处方例2-1>保健食品的制备
在将1㎎HAPLN1、维生素混合物适当量(70μg维生素A乙酸酯、1.0㎎维生素E、0.13㎎维生素B1、0.15㎎维生素B2、0.5㎎维生素B6、0.2μg维生素B12、10㎎维生素C、10μg生物素、1.7mg烟酰胺、50μg叶酸、0.5mg泛酸钙)和矿物质混合物适当量(1.75mg硫酸亚铁、0.82mg氧化锌、25.3mg碳酸镁、15mg磷酸一钾、55mg磷酸氢二钙、90mg柠檬酸钾、100mg碳酸钙、24.8mg氯化镁)混合后制备颗粒，并根据常规方法制备保健食品。
<处方例2-2>保健饮料的制备
通过添加1㎎HAPLN1、1000㎎柠檬酸、100g寡糖、2g梅子浓缩物、1g克牛磺酸和纯净水来制成总量达到900ml的溶液，并根据常规的保健饮料制备方法来搅拌所述成分，然后在85℃搅拌和加热1小时，并将所得溶液过滤以放置在无菌的2L容器中，并密封并灭菌后进行冷藏保管。
如以上详细描述的本发明的特定部分，对于本领域技术人员显而易见的是，如此具体的技术说明仅是优选实施例，并且本发明的范围不限于此。因此，本发明的实质范围将由所附权利要求及其等同物来定义。
本发明的范围由所附的权利要求书表示，并且应该解释为，从权利要求书的含义和范围及其等同概念得出的所有改变或修改都包括在本发明的范围内。
Claims (6)
1.透明质酸和蛋白聚糖连接蛋白1(HAPLN1)在制备用于提高软骨细胞中TGF-β受体I含量或增加软骨细胞中TGF-β受体I稳定性的药物组合物中的用途。
2.根据权利要求1所述的用途，其特征在于，所述HAPLN1促进软骨形成并保护关节软骨。
3.根据权利要求1所述的用途，其特征在于，所述HAPLN1通过提高TGF-β受体I的表达水平来增加具有软骨形成能力的细胞的组成比并诱导软骨组织再生。
4.透明质酸和蛋白聚糖连接蛋白1(HAPLN1)在制备用于提高软骨细胞中TGF-β受体I含量或增加软骨细胞中TGF-β受体I稳定性的保健食品组合物中的用途。
5.透明质酸和蛋白聚糖连接蛋白1(HAPLN1)在制备用于提高软骨细胞中TGF-β受体I含量或增加软骨细胞中TGF-β受体I稳定性的试料组合物中的用途。
6.一种通过使用透明质酸和蛋白聚糖连接蛋白1(HAPLN1)来在体外提高软骨细胞中TGF-β受体I含量或增加软骨细胞中TGF-β受体I稳定性的方法，其中所述方法用于非治疗目的。
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| KR1020180098497A KR20190024727A (ko) | 2017-08-29 | 2018-08-23 | Hapln1을 유효성분으로 함유하는 연골 재생용 조성물 |
| PCT/KR2018/009996 WO2019045451A1 (ko) | 2017-08-29 | 2018-08-29 | Hapln1을 유효성분으로 함유하는 연골 재생용 조성물 |
| CN201880056630.7A CN111295194A (zh) | 2017-08-29 | 2018-08-29 | 一种包括hapln1作为有效成分的用于软骨再生的组合物 |
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| CN201880056630.7A Pending CN111295194A (zh) | 2017-08-29 | 2018-08-29 | 一种包括hapln1作为有效成分的用于软骨再生的组合物 |
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| KR20190024727A (ko) | 2017-08-29 | 2019-03-08 | 중앙대학교 산학협력단 | Hapln1을 유효성분으로 함유하는 연골 재생용 조성물 |
| US20230158106A1 (en) * | 2019-02-28 | 2023-05-25 | Haplnscience inc. | Composition for preventing, relieving or treating cartilage-related diseases or symptoms, comprising hapln1 |
| BR112021021860A2 (pt) * | 2019-04-30 | 2021-12-21 | Haplnscience Inc | Composição farmacêutica e composição cosmética para prevenir ou tratar a perda de cabelo |
| KR102390418B1 (ko) * | 2019-04-30 | 2022-04-26 | 주식회사 하플사이언스 | Hapln1을 포함하는 탈모 예방 또는 치료용 조성물 |
| KR102284800B1 (ko) | 2020-12-30 | 2021-08-03 | 주식회사 하플사이언스 | 재조합 세포외 기질 단백질의 생산을 위한 동물세포 배양용 배지 조성물 및 이를 이용한 방법 |
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| US20080139500A1 (en) * | 2006-12-11 | 2008-06-12 | Isadore Elliott Goldberg | Use of composite monomer or monomers, catalyst, sodium hyaluronate or hyaluronic acid, glucosamide sulfate, chondroiten sulfate or chlorides, for the treatment of osteoarthritis by intraarticular application to a hip or knee joint |
| SG177694A1 (en) | 2009-07-16 | 2012-02-28 | Biotime Inc | Methods and compositions for in vitro and in vivo chondrogenesis |
| US20130052198A1 (en) * | 2010-03-29 | 2013-02-28 | The General Hospital Corporation | Anti-inflammatory factors |
| JP5767591B2 (ja) | 2012-01-24 | 2015-08-19 | ＨＯＹＡ Ｔｅｃｈｎｏｓｕｒｇｉｃａｌ株式会社 | 人工軟骨の製造方法 |
| US20140178988A1 (en) | 2012-10-08 | 2014-06-26 | Biotime, Inc. | Differentiated Progeny of Clonal Progenitor Cell Lines |
| WO2014130411A1 (en) | 2013-02-22 | 2014-08-28 | Emory University | Tgf-beta enhancing compositions for cartilage repair and methods related thereto |
| JP2016531147A (ja) * | 2013-09-09 | 2016-10-06 | フィジーン、エルエルシーＦｉｇｅｎｅ， Ｌｌｃ | コンドロサイトまたは軟骨型細胞の再生のための遺伝子治療 |
| KR101897340B1 (ko) * | 2015-09-09 | 2018-09-13 | 중앙대학교 산학협력단 | Hapln1을 이용한 피부 노화 측정 또는 예방 또는 개선용 조성물 |
| EP3402534A4 (en) * | 2016-01-14 | 2019-09-18 | Spinalcyte, LLC | CELLULAR MIXTURE FOR REGENERATING CHONDROCYTES OR CARTILES |
| KR20190024727A (ko) | 2017-08-29 | 2019-03-08 | 중앙대학교 산학협력단 | Hapln1을 유효성분으로 함유하는 연골 재생용 조성물 |
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| ES2913411T3 (es) | 2022-06-02 |
| EP3677269A4 (en) | 2021-04-28 |
| US11213572B2 (en) | 2022-01-04 |
| EP3677269A1 (en) | 2020-07-08 |
| EP3677269B1 (en) | 2022-04-27 |
| JP2020531560A (ja) | 2020-11-05 |
| KR20190024727A (ko) | 2019-03-08 |
| CN111295194A (zh) | 2020-06-16 |
| US20200276278A1 (en) | 2020-09-03 |
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