CN114786702A - 用于促进成骨细胞功能和骨愈合的血栓调节蛋白功能域 - Google Patents
用于促进成骨细胞功能和骨愈合的血栓调节蛋白功能域 Download PDFInfo
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Abstract
本发明涉及用于促进成骨细胞功能和骨愈合的血栓调节蛋白功能域。本发明公开了用于刺激骨再生、骨增强，治疗骨丢失、骨病症和/或治疗骨相关病症的方法。所述方法包括向有需要的受试者施用治疗有效量的(I)：包含与人血栓调节蛋白结构域2和3(TMD23)具有至少80％同一性的氨基酸序列的生物活性重组多肽；(II)：包含重组TMD23(rTMD23)的分离多肽或其生物活性重组变体；或(III)：重组TMD23(rTMD23)或其生物活性重组变体，其中所述多肽不含或缺乏来自人血栓调节蛋白结构域4和5的氨基酸残基，并且进一步地，其中所述其生物活性变体包含与TMD23具有至少80％同一性的氨基酸序列。
Description
技术领域
本发明总体上涉及治疗骨丢失、促进骨形成和骨折修复(骨诱导、骨增强)，更具体地涉及刺激成骨细胞生成和抑制破骨细胞生成的方法。
背景技术
骨重塑过程涉及破骨细胞对矿化骨的吸收，然后是骨基质的形成和成骨细胞的矿化。在生长因子和维生素D3的刺激下，间充质干细胞转化为骨祖细胞和成骨细胞以启动成骨。成骨细胞分泌I型胶原蛋白和钙沉积形成类骨质，进一步矿化形成骨组织。另一方面，在巨噬细胞集落刺激因子1(M-CSF)和核因子κB(NFκB)受体活化因子配体(RANKL)的刺激下，巨噬细胞转化形成破骨细胞，其负责骨吸收过程，称为破骨细胞生成。骨吸收和形成过程之间的平衡对于维持骨的稳态至关重要。
骨质疏松症是由于破骨细胞和成骨细胞的重塑活动之间的不平衡而导致骨的质量或密度降低时发生的疾病。可用于预防和/或治疗骨质疏松症的药物包括双膦酸盐、降钙素、雌激素(激素疗法)、雌激素激动剂、甲状旁腺激素(PTH)类似物、RANK配体(RANKL)抑制剂和组织选择性雌激素复合物(TSEC)。这些药物有副作用，不能同时刺激成骨细胞生成和抑制破骨细胞生成。
人血栓调节蛋白(TM)是一种跨膜蛋白，其结构由5个结构域组成，包括NH2末端凝集素样结构域(D1)、具有6个表皮生长因子(EGF)样结构的结构域(D2)、富含O-糖基化位点的结构域(D3)、跨膜结构域(D4)和胞质尾结构域(D5)。Cheng等人报道称，TMD1可以通过减少促炎高迁移率组框1(HMGB1)信号传导来抑制破骨细胞生成(“Myeloid thrombomodulinlectin-like domain inhibits osteoclastogenesis and inflammatory bone loss”SciRep.2016；6:28340)。
美国专利号9,968,660公开了骨再生或骨增强的方法。
发明内容
一方面，本发明涉及包含与人血栓调节蛋白结构域2和3(TMD23)具有至少80％同一性的氨基酸序列的生物活性重组多肽在制备用于在有需要的受试者中刺激骨再生、骨增强，治疗骨丢失、骨病症和/或骨相关病症的药物中的用途，其中所述多肽不含或缺乏来自人血栓调节蛋白结构域4和5的氨基酸残基。
另一方面，本发明涉及包含重组的人血栓调节蛋白结构域2和3(rTMD23)的分离多肽或其生物活性重组变体在制备用于在有需要的受试者中刺激骨再生、骨增强，治疗骨丢失、骨病症和/或骨相关病症的药物中的用途，其中，其生物活性变体包含与TMD23具有至少80％同一性的氨基酸序列，并且进一步地，其中，所述多肽不含或缺乏来自人血栓调节蛋白结构域4和5的氨基酸残基。
在一个实施方式中，所述多肽包含TMD23的氨基酸残基。
在另一个实施方式中，所述多肽包含SEQ ID NO:1的224Ala至497Ser，或1Ala至497Ser的氨基酸残基。
在另一个实施方式中，所述多肽包含SEQ ID NO:3的氨基酸序列。
在另一个实施方式中，所述多肽是生物活性重组TMD23变体并且包含SEQ ID NO:3的氨基酸序列。
在另一个实施方式中，所述多肽还包含来自人血栓调节蛋白结构域1的氨基酸残基。
在一个实施方式中，所述多肽基本上由人血栓调节蛋白结构域2和3，或结构域1、2和3组成。
在另一个实施方式中，所述重组TMD23变体由SEQ ID NO:3的氨基酸序列组成。
在另一个实施方式中，所述多肽包含选自SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4和SEQ ID NO:5的氨基酸序列。
在另一个实施方式中，所述多肽或所述生物活性变体包含与rTMD23具有至少85％、或至少90％、或至少95％同一性的氨基酸残基。
在另一方面，本发明涉及重组的人血栓调节蛋白结构域2和3(rTMD23)或其生物活性重组变体在制备用于在需要的受试者中刺激骨再生、骨增强，治疗骨丢失、骨病症和/或骨相关病症的药物中的用途，其中其生物活性变体包含与人TMD23具有至少80％同一性的氨基酸序列。
在另一个实施方式中，rTMD23的重组变体包含SEQ ID NO:3的氨基酸序列。
在另一个实施方式中，重组TMD23变体由SEQ ID NO:3的氨基酸序列组成。
在另一个实施方式中，所述骨病症是选自骨质疏松症、骨丢失、未能实现最佳骨形成、未能实现最佳骨折愈合、骨骼生长期间达到低峰值骨量、受损新骨形成以及它们的任何组合的疾病或病症。
在另一个实施方式中，所述骨相关病症选自甲状旁腺功能亢进、甲状旁腺功能亢进相关的骨量减少、甲状旁腺功能亢进相关的骨密度降低、骨质减少、骨丢失、炎性骨丢失、骨质疏松症、老年骨质疏松症、绝经后骨质疏松症、糖皮质激素诱导的骨质疏松症、颌骨坏死、佩吉特病和高磷血症中的至少一种。
此外，在另一个实施方式中，上述用途与骨移植材料的使用相组合用于制备用于刺激新骨形成的药物。骨移植材料提供结构稳定性和连接，并刺激骨折中的成骨和骨愈合。
如前所述的多肽或rTMD23的生物活性重组变体可用于制备用于治疗骨相关病症、刺激骨修复、促进骨植入物植入或刺激成骨细胞增殖的药物。
在一个实施方式中，药物呈适合应用于需要骨增强的身体部位的剂型。
需要骨增强的身体部位选自窦底提升、骨移植和脊扩张中的一种。
药物可以是凝胶、乳膏、糊剂、洗剂、喷雾剂、悬浮液、溶液、分散油膏、水凝胶或软膏形式。
在另一个实施方式中，需要骨增强的身体部位选自需要骨修复、骨折愈合或脊柱融合的部位。
在一个实施方式中，需要骨增强的身体部位是种植牙放置部位。
药物可以是含有人每日剂量的上述多肽的剂型，单位剂量范围为100ng/kg至100mg/kg×(0.025kg/人体重kg)0.33。
本发明还涉及用于刺激骨再生、骨增强，治疗骨丢失、骨病症和/或骨相关病症的方法。所述方法包括向有需要的受试者施用治疗有效量的(I)：包含与TMD23具有至少80％同一性的氨基酸序列的生物活性重组多肽；(II)：包含重组TMD23(rTMD23)的分离多肽或其生物活性重组变体；或(III)：重组TMD23(rTMD23)或其生物活性重组变体，其中所述多肽不含或缺乏来自人血栓调节蛋白结构域4和5的氨基酸残基，并且所述其生物活性变体包含与TMD23具有至少80％同一性的氨基酸序列。
或者，本发明涉及(I)：包含与人TMD23具有至少80％同一性的氨基酸序列的生物活性重组多肽；(II)：包含重组TMD23(rTMD23)的分离多肽或其生物活性重组变体；或(III)：重组TMD23(rTMD23)或其生物活性重组变体，用于在有需要的受试者中刺激骨再生、骨增强，治疗骨丢失、骨病症和/或骨相关病症，其中所述多肽不含或缺乏来自人血栓调节蛋白结构域4和5的氨基酸残基，并且进一步地，其中其生物活性变体包含与TMD23具有至少80％同一性的氨基酸序列。
通过结合以下附图对优选实施方式的以下描述，这些和其他方面将变得显而易见，尽管其中的变化和修改可能会受到影响，而不会偏离本发明新颖概念的精神和范围。
附图说明了本发明的一个或多个实施方式，并与书面描述一起用于解释本发明的原理。在可能的情况下，在整个附图中使用相同的附图标记来指代实施方式的相同或类似元件。
附图说明
图1A-B显示重组TMD23(rTMD23)和TMD123促进MG63细胞的细胞迁移。将MG63细胞装入上室，并将所示的各种浓度的rTMD23或TMD123装入下室。孵育4小时后，用Liu染色法对膜进行染色。拍照后对迁移的细胞进行计数。**P<0.01。
图2A显示重组TMD23(rTMD23)增强MG-63细胞的细胞增殖。**P<0.01；***P<0.001。
图2B显示重组TMD23NA，一种rTMD23的变体，增强了MC3T3-E1细胞的细胞增殖。*与0ng/ml rTMD23NA的吸光度相比，P<0.05。
图3显示重组TMD23(rTMD23)增强MG-63细胞的细胞矿化。将细胞用不同浓度的rTMD23(0、10、25、50ng/mL)孵育28天。细胞用10％甲醛固定20分钟，然后在染色前用PBS洗涤两次。将茜素红S(40％)以1000μL/孔添加到每孔中静置20分钟，然后用ddH2O冲洗至少五次。用10倍量级倒置荧光显微镜拍摄照片，用ImageJ软件测量相对强度。***P<0.001。
图4A-B显示rTMD123抑制RAW264.7细胞上RANKL诱导的破骨细胞形成。(4A)将RAW264.7细胞在RANKL(30ng/ml)和M-CSF(20ng/ml)存在下用指定浓度的rTMD123培养4天。用TRAP染色观察多核破骨细胞。(4B)对TRAP+OC计数。***P<0.001(与MCSF/RANKL治疗组相比)。数据以平均值±标准差表示，并代表至少三个实验。
图5A-D显示rTMD23(5A-B)及其变体(5C-D)分别抑制RAW264.7细胞中RANKL诱导的破骨细胞形成。在RANKL和M-CSF存在下用指定浓度的rTMD23或变体rTMD23NA培养RAW264.7细胞4天。用TRAP染色观察多核破骨细胞。对每孔中的TRAP+OC计数。数据以平均值±标准差表示，并代表至少三个实验。***P<0.001(与MCSF/RANKL治疗组相比)。
图6A-B显示rTMD123对吸收坑形成的影响。(6A)将RAW264.7细胞在含有不同浓度rTMD123的Corning Osteoassay 96孔板上，在MCSF(20ng/ml)和RANKL(30ng/ml)存在下培养4天。孵育后，用光学显微镜观察板上的吸收陷窝。(6B)使用Image J软件计算相对于对照组的再吸收面积百分比。***P<0.001(与MCSF/RANKL治疗组相比)。
图7A-B显示重组TMD23(rTMD23)增强STZ小鼠的颅骨愈合。小鼠每天注射50mg/kg链脲佐菌素(STZ)至少五天。最后一次注射后3天测量血糖。然后进行颅骨手术，形成一个直径为4mm的洞。(7A)术后第7天(第1周)局部皮下注射rTMD23(0、10、100μg/kg)一次，并在第0周和第8周拍摄微CT(μCT)图像。(7B)对于数据量化，术语“TV”代表洞的总体积，术语“BV”代表第8周的再生骨体积。**P<0.01。
图8A-F显示TMD1和TMD23对颅骨愈合的影响。用指定剂量的rTMD1处理的MG63细胞的(8A)细胞迁移，(8B)增殖和(8C)矿化。(8D)TM野生型TMwt/wt和TM结构域1(TMD1)缺失的TMLeD/LeD小鼠的颅骨愈合。(8E)μCT扫描和(8F)HE染色用于评估介质、二氯异香豆素(DCI)和DCI加rTMD23或rTMD1(100μg/kg)对小鼠颅骨缺损后骨愈合的影响。N＝5/组。黑条＝100μm、白条＝1mm。虚线表示截面区域。***P<0.001。
具体实施方式
以下实施例更具体地描述了本发明，这些实施例仅用于说明，因为本领域技术人员将显而易见地得到其中的许多修改和变化。现在详细描述本发明的各种实施方式。参考附图，相似的附图标记表示整个视图中的相似部件。如在本文的描述中以及在随后的权利要求中所使用的，“一”、“一种”和“该”的含义包括复数引用，上下文另有明确规定的除外。此外，如在本文的描述中以及在随后的所有权利要求中所使用的，“在……中”的含义包括“在……中”和“在……上”，上下文另有明确规定的除外。此外，为了方便读者，可以在说明书中使用标题或副标题，这不应影响本发明的范围。此外，本说明书中使用的一些术语在下文中有更具体的定义。
定义
本说明书中使用的术语在本领域、在本发明的上下文中以及在使用每个术语的特定上下文中通常具有其普通含义。下文或说明书中的其他地方讨论了用于描述本发明的某些术语，以就本发明的描述向从业者提供额外的指导。将理解同样的事物可以用不止一种方式来表达。因此，本文中讨论的任何一个或多个术语都可以使用替代语言和同义词，本文中是否详细阐述或讨论了一个术语不赋予任何特殊意义。提及一个或多个同义词并不排除使用其他同义词。本说明书中任何地方的实施例(包括本文讨论的任何术语的实例)的使用仅是说明性的，并且不以任何方式限制本发明或任何示例性术语的范围和意义。同样，本发明不限于本说明书中给出的各种实施方式。
除非另有定义，本文中使用的所有技术和科学术语具有本发明所属领域的普通技术人员通常理解的含义。如有冲突，以本文件(包括定义)为准。
如本文所用，“约(around)”、“大约(about)”或“近似(approximately)”通常指给定值或范围的20％以内，优选10％以内，更优选5％以内。本文给出的数值是近似值，这意味着如果没有明确说明，可以推断术语“约(around)”、“大约(about)”或“近似(approximately)”。
术语“rTMD23”指重组的血栓调节蛋白结构域2和3。血栓调节蛋白(TM)是一种细胞膜结合糖蛋白，由五个结构域组成，包括N端凝集素样结构域(D1)、6个表皮生长因子(EGF)重复序列(D2)、丝氨酸-苏氨酸富集区(D3)、跨膜结构域(D4)和短胞质尾(D5)。不含信号肽的成熟人TM具有557个氨基酸残基，包含SEQ ID NO:1的氨基酸序列。
至少80％意味着80％到100％范围内的所有整数单位量都作为本发明的一部分具体公开。因此，包含80％、81％、82％、83％、84％、85％……88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％和100％单位量作为本发明的实施方式。
术语“与TMD23具有至少80％同一性的氨基酸序列”应包含野生型rTMD23及其生物活性重组变体。
术语“生物活性的(bioactive)”和“生物活性地(biologically active)”可以互换。
如本文所用，术语“其生物活性重组变体”通常指血栓调节蛋白结构域2和3(TMD23)的生物活性重组变体形式。
“rTMD23的生物活性重组变体”是指具有野生型rTMD23生物活性的变体，其中生物活性是选自促进成骨细胞中的细胞增殖和迁移、增强成骨细胞中的细胞矿化、抑制破骨细胞生成、抑制骨吸收活性、促进骨再生、促进成骨细胞功能和骨愈合中的至少一种，及其任何组合。
术语“重组TMD23的生物活性变体形式”、“生物活性重组人TMD23变体”、“生物活性重组人TMD23变体多肽”和“人rTMD23变体”可以互换。
如本文所用，术语“血栓调节蛋白变体”、“血栓调节蛋白的变体”和“突变型血栓调节蛋白”可以互换。
血栓调节蛋白的变体通常指氨基酸残基与野生型血栓调节蛋白结构域不同但保留野生型血栓调节蛋白结构域在促进伤口愈合效果方面的生物活性的突变型血栓调节蛋白。此类血栓调节蛋白变体，rTMD23NA和rTMD123NA已在美国专利号9,156,904B2中公开，所有这些均通过引用整体并入本文。
术语“rTMD23NA”指带有两个替换Asn364Ala和Asn391Ala的重组TMD23变体。rTMD23NA是一种突变体，其在野生型成熟人血栓调节蛋白(SEQ ID NO:1)的第364和391位残基处，Asn被Ala取代。
TMD123NA和rTMD23NA都是具有两个假定的N-糖基化Asn残基，即TMD23的N364和N391通过定点突变技术突变为Ala的变体。重组突变体rTMD23NA具有很少或没有蛋白C激活活性。优选地，血栓调节蛋白的变体包含和/或具有以下特征：(i)与SEQ ID NO:1(557aa)具有至少80％同一性的氨基酸序列；(ii)两个氨基酸残基替换Asn364Ala和Asn391Ala；(iii)很少或没有蛋白C激活活性。
术语“治疗(treating)”或“治疗(treatment)”是指向患有疾病或具有此类疾病症状或倾向的受试者施用有效量的治疗剂，目的是治疗、缓解、减轻、补救、改善或预防疾病、其症状或倾向。
术语“骨移植材料(bone grafting materials)”和“骨移植材料(bone graftmaterials)”可以互换。众所周知，骨移植材料可提供结构稳定性和连接，并刺激骨折中的成骨和骨愈合。
术语“与……相关”通常指“与……有关”或“关于”。因此，“与骨量减少相关的甲状旁腺机能亢进症”应指“与骨量减少有关的甲状旁腺机能亢进症”。
美国卫生部和人服务部食品和药物管理局发布的《行业和审查人员评估成人健康志愿者治疗学临床试验安全起始剂量指南》中披露，“人体等效剂量”可通过以下公式计算得出：
HED＝以mg/kg计的动物剂量×(以kg计的动物体重/以kg计的人体重)0.33。
序列表：SEQ ID NO:1，不含信号肽的野生型全长TM氨基酸序列(557aa)；结构域1，1Ala-223Gly；结构域2，224Ala-462Cys；结构域3，463Asp-497Ser；结构域4，498Gly-521Leu；结构域5，522Arg-557Leu；SEQ ID NO:2，rTMD23序列(274aa)；SEQ ID NO:3，rTMD23NA序列(274aa)；SEQ ID NO:4，rTMD123序列(497aa)；SEQ ID NO:5，TMD123NA序列(497aa)。
缩写：TM，血栓调节蛋白；rTM，重组血栓调节蛋白；rTMD23，重组血栓调节蛋白结构域2和3；TMD4，血栓调节蛋白结构域4；TMD5，血栓调节蛋白结构域5；Asn(N)，天冬酰胺；Ala(A)，丙氨酸。
本发明涉及包含血栓调节蛋白结构域2和3(TMD23)或其变体的截短血栓调节蛋白(TM)蛋白质的发现，该蛋白质具有抑制巨噬细胞转化为破骨细胞并促进间充质干细胞形成成骨细胞的生物活性。研究发现，截短的TM蛋白TMD23、TMD123和变体TMD23NA可同时增加成骨细胞的生成和抑制破骨细胞的生成。这些具有生物活性的TM结构域可用于刺激骨形成和抑制骨丢失。
本发明还涉及重组蛋白TMD23、TMD123或其生物活性变体，其用于改善和治疗骨质疏松症。研究发现，在重组TM片段中，TM结构域2和3(TMD23)而不是凝集素样结构域(TMD1)促进成骨细胞功能和颅骨愈合。本发明还涉及一种截短的TM，其用于通过全身、局部给药或与骨移植材料组合来刺激成骨细胞，同时抑制破骨细胞。
实施例
在不限制本发明范围的情况下，下面给出根据本发明实施方式的示例性仪器、装置、方法及其相关结果。注意，为了方便读者，可以在实施例中使用标题或副标题，这不应限制本发明的范围。此外，本文还提出并披露了某些理论；然而，只要根据本发明实施本发明而不考虑任何特定的理论或行动方案，无论它们对错与否，均不应限制本发明的范围。
材料和方法
重组TM结构域和变体蛋白的表达和纯化。rTMD23和变体rTMD23NA的制备已在U.S.9,156,904B2中公开，其全文通过引用并入本文。简而言之，pCR3或pPICZA载体(Invitrogen,Oregon)用于在HEK293或毕赤酵母(Pichia pastoris)蛋白表达系统中表达和分泌重组TM结构域蛋白。编码TMD1、TMD23和TMD123的DNA片段如前所述获得(Shi等人“Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Yantigen and neutralizes lipopolysaccharide-induced inflammatory response”Blood.2008年11月1日；112(9):3661-70；Cheng等人“Functions of rhomboid familyprotease RHBDL2and thrombomodulin in wound healing”J Invest Dermatol.2011年12月；131(12):2486-94)。将表达的重组蛋白上样于镍螯合Sepharose柱，洗脱含有重组TM结构域的级分。
细胞培养和处理。使用成骨细胞系MC3T3-E1、人成骨样细胞系MG63和小鼠巨噬细胞系RAW264.7(
Rockville,MD,USA)。所有细胞均在含有10％的胎牛血清(FBS，Gibco)的Dulbecco改良的Eagle培养基(DMEM，Gibco，MD，USA)中培养。
Transwell细胞迁移测定。使用具有8-μm孔径膜的24孔趋化室来评估细胞迁移。将细胞悬浮液(对于MG63细胞，5×104细胞/100μL的无血清DMEM培养基)添加到上腔，并将无血清培养基(600μL)中的重组TM结构域添加到下腔。将这些腔室在37℃下孵育8小时。未迁移的细胞用棉板擦掉。使用刘氏染色试剂盒使过滤器显色，并在显微镜下计数剩余细胞的数量。
增殖测定。将MG63细胞用不同浓度的rTMD23处理1、4、7天。每2-3天更换培养基。最后，用结晶紫法测定每孔中活细胞的数量。每孔中的细胞在染色前用PBS清洗两次。在每孔中加入结晶紫(0.5％，300μL)15分钟，然后用ddH2O冲洗至少五次。加入醋酸(10％，300μL)以溶解结晶紫。然后，取100μL/孔置于96孔板中，以获得OD595测量值。进行不同浓度TMD23变体下的MC3T3-E1细胞增殖测定。简而言之，将96孔板中的MC3T3-E1细胞用不同浓度的rTMD23NA处理1、3、5天。使用WST-1试剂测量每孔中的活细胞数。每孔中的细胞用DMEM培养基洗涤两次，然后用100μL 10％的WST-1(在DMEM中)染色。测量每孔在A450nm-A690nm处的吸光度。
矿化测定。将MG63细胞接种在6孔板(5×105个细胞/孔)中，并用重组TM结构域处理28天。如前所述，使用茜素红染色法对矿化基质进行钙染色(Stanford等人“Rapidlyforming apatitic mineral in an osteoblastic cell line(UMR 106-01BSP)”J BiolChem.1995年4月21日；270(16):9420-8)。简单地说，用PBS清洗细胞，然后在冰冷的70％乙醇中固定1小时。洗涤后，在室温下用40mM茜素红(pH 4.2)染色细胞10分钟。染色细胞进一步如下处理：用水冲洗五次，然后在PBS中旋转15分钟洗涤，以减少非特异性茜素红染色。拍摄图像并通过ImageJ软件测量相对强度。
实验动物和糖尿病小鼠。使用缺乏TM凝集素样结构域(TMLeD/LeD)的六至八周龄小鼠和野生型C57BL/6小鼠(Conway等人“The lectin-like domain of thrombomodulinconfers protection from neutrophil-mediated tissue damage by suppressingadhesion molecule expression via nuclear factor kappaB and mitogen-activatedprotein kinase pathways”J Exp Med.2002年9月2日；196(5):565-77)。通过单次静脉注射溶解于50mM柠檬酸盐(pH 4.7)中的链脲佐菌素(STZ)(150mg/kg)产生糖尿病小鼠。对照组小鼠注射柠檬酸盐缓冲液。使用葡萄糖试剂盒(Randox,Crumlin,UK)根据制造商的说明测量葡萄糖含量。糖尿病小鼠的血糖浓度达到413.9mm(250mg/dL)。
颅骨缺损愈合。雄性小鼠被随机分配到指定的组。麻醉后，在颅骨上形成直径为4mm的缺损，并缝合伤口。术后第1周，在颅骨开口附近皮下注射一次二氯异香豆素(DCI)(1mM)或rTMD23(0、10、100μg/kg)和U0126(20μM)的组合。在术后指定的时间点(第0周和第8周)，使用μCT(Skyscan1076,Antwerp,Belgium)放射照相和组织学监测骨愈合情况。μCT扫描仪在50kV、220mA、1.2s曝光时间下运行，像素尺寸为2.5mm，铝滤光片为0.5mm，通过180°旋转产生同位素17.09mm体素，切片厚度为2.5mm。为了计算骨形成，选择直径为4mm、深度为2mm的圆柱形体积进行颅骨缺损再生。使用NRecon程序(Skyscan)将断层图像转换为体积重建。通过3D CT分析仪软件(CTAN；Skyscan)对除去和再生的骨体积(mm3)进行量化。
为了进行组织学分析，将标本在10％EDTA中脱钙1周，然后包埋在石蜡中。采用10mm厚的切片进行苏木精-伊红(H&E)染色。
统计分析。使用Prism 7(GraphPad软件)进行统计分析。数据以平均值±标准差表示。对于多组的比较，采用单因素方差分析(ANOVA)。对于不同时间点的多组比较，使用双因素方差分析。P<0.05的值被认为具有统计学意义。
结果
rTMD23和rTMD123均能促进成骨细胞的细胞迁移
成骨细胞的细胞功能包括迁移、增殖和矿化。将无血清培养基中的细胞添加到上层transwell腔中，在下层transwell腔中添加1％胎牛血清和增加剂量的rTMD23。37℃孵育4小时后，取下transwell膜并染色。在显微镜下计数通过膜迁移到膜下表面的细胞数量。细胞迁移测定显示，rTMD23和rTMD123均增加了成骨细胞的细胞迁移(图1A-B)。
rTMD23及其生物活性变体均促进成骨细胞的细胞增殖
采用人成骨样细胞系MG63和成骨细胞系MC3T3-E1进行细胞增殖测定。简而言之，将不同浓度的rTMD23和rTMD23NA(rTMD23的变体形式)分别添加到含有1％FBS的MG63或MC3T3-E1细胞培养物中。将细胞培养物用PBS洗涤两次，并用结晶紫染色。测量10％乙酸中细胞裂解物的OD595，以获得每孔中的相对细胞计数。结果表明，rTMD23和变体rTMD23NA分别能增强人成骨样细胞系MG63(图2A)和成骨细胞系MC3T3-E1(图2B)的细胞增殖。
rTMD23增强成骨细胞的细胞矿化
将MG63细胞在含有1％FBS的培养基中，在指示的浓度的rTMD23存在下，孵育28天。用10％甲醛固定后，用40％茜素红S染色细胞。结果表明rTMD23可促进MG63细胞的矿化(图3)。
rTMD123、rTMD23及其变体均抑制破骨细胞生成
为诱导破骨细胞生成，将RAW264.7细胞在RANKL(30ng/ml)和M-CSF(20ng/ml)存在下培养4天，以诱导TRAP阳性破骨细胞的形成。每个孔中的多核破骨细胞用TRAP染色法显示(图4A)。对每孔中形成的TRAP+OC的数量计数(图4B)。在rTMD123存在的情况下，TRAP阳性破骨细胞的形成受到抑制。rTMD23(图5A-B)和变体rTMD23NA(图5C-D)也获得了类似的结果。结果表明，rTMD23和rTMD123均能抑制体外破骨细胞的生成。
rTMD123抑制破骨细胞的骨吸收活性
在不同浓度的rTMD123存在下，用MCSF(20ng/ml)和RANKL(30ng/ml)诱导在Corning Osteoassay 96孔板上培养的RAW264.7细胞形成破骨细胞。孵育4天后，使用光学显微镜观察每个孔上的吸收陷窝(图6A)，并使用Image J软件测量吸收面积。与对照组相比，rTMD123治疗组的骨吸收面积百分比显著降低(图6B)。结果表明，rTMD123可以抑制RAW264.7细胞的骨吸收活性。
rTMD23增强链脲佐菌素诱导的糖尿病模型的颅骨愈合
通过注射50mg/kg链脲佐菌素(STZ)5天诱导小鼠患糖尿病。在每只小鼠的颅骨上生成一个直径为4mm的洞。术后第1周，在颅骨开口附近皮下注射不同剂量的rTMD23一次。在第0周和第8周拍摄微CT图像(图7A)。rTMD23治疗组在8周内再生的骨体积显著增加(图7B)。结果表明，rTMD23能促进骨再生。小鼠的平均体重为25g。
rTMD23而不是rTMD1促进颅骨愈合
我们进一步研究了TM凝集素样结构域(TMD1)是否也能增强成骨细胞的细胞功能。功能测定表明，rTMD1不促进MG63细胞中的细胞迁移(图8A)、或增殖(图8B)、或矿化(图8C)。使用缺失TMD1(TMLeD/LeD)的转基因小鼠，通过颅骨愈合测定进一步评估TMD1对骨再生的影响。正如μCT显示，在第8周，TMLeD/LeD小鼠和TM野生型TMwt/wt对照小鼠之间的骨愈合没有显著差异(图8D)。这些发现表明TMD1不能促进成骨细胞功能和骨愈合。颅骨愈合测定也用于评估TMD23对骨愈合的影响。μCT测量(图8E)和H&E染色(图8F)均显示，用DCI抑制RHBDL2和TM胞外域脱落的治疗减少了颅骨缺损的再生。然而，rTMD23可以补救这种抑制作用，但rTMD1不能。结果表明，rTMD23而非rTMD1具有促进成骨细胞功能和骨愈合的能力。
总之，rTMD23、rTMD123或其变体可促进成骨细胞的迁移、增殖和矿化。如所示出的那样，TMD23可以作为化学引诱剂吸引成骨细胞和前成骨细胞MG63(一种人成骨细胞样细胞系)，从而促进骨形成。MG63细胞表型上处于前成骨细胞状态，可被诱导矿化。证明TMD23可促进STZ诱导的糖尿病小鼠的骨愈合。在破骨细胞生成过程中用巨噬细胞集落刺激因子1(MCSF-1)和RANK配体(RANKL)刺激可诱导巨噬细胞形成多核破骨细胞。TMD23、TMD123或其生物活性变体可抑制MCSF-1和RANK配体(RANKL)诱导的巨噬细胞破骨细胞生成。如所示出的那样，rTMD23可以抑制破骨细胞的骨吸收。
总之，含有血栓调节蛋白结构域23的蛋白质，包括TMD23、TMD123及其生物活性变体，可以抑制破骨细胞生成并促进成骨细胞生成。TMD23、TMD123或其生物活性变体可用于预防和治疗骨丢失疾病、症状或病症，包括骨质疏松症、骨质减少症、类风湿性关节炎、关节炎和牙周炎，并用于促进骨再生、骨增强、骨损伤治疗和促进骨愈合。
对本发明的示例性实施方式的前述描述仅出于说明和描述的目的而呈现，并不旨在穷尽或将本发明限制于所公开的精确形式。根据上述教学，许多修改和变化是可能的。
在本发明的说明书中引用和讨论了一些参考文献，这些参考文献可能包括专利、专利申请和各种出版物。引用和/或讨论这些参考文献仅仅是为了澄清本发明的描述，而不是承认任何此类参考文献是本文所述发明的“现有技术”。本说明书中引用和讨论的所有参考文献的全部内容通过引用并入本文，其并入程度与每个参考文献通过引用单独并入的程度相同。
SEQUENCE LISTING
<110> 宝血纯化科技股份有限公司
<120> 用于促进成骨细胞功能和骨愈合的血栓调节蛋白功能域
<130> 10035-005PCT
<150> 62951490
<151> 2019-12-20
<160> 5
<170> PatentIn version 3.5
<210> 1
<211> 557
<212> PRT
<213> 智人(Homo sapiens)
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Ala Pro Ala Glu Pro Gln Pro Gly Gly Ser Gln Cys Val Glu His Asp
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Cys Phe Ala Leu Tyr Pro Gly Pro Ala Thr Phe Leu Asn Ala Ser Gln
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Ile Cys Asp Gly Leu Arg Gly His Leu Met Thr Val Arg Ser Ser Val
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Ala Ala Asp Val Ile Ser Leu Leu Leu Asn Gly Asp Gly Gly Val Gly
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Arg Arg Arg Leu Trp Ile Gly Leu Gln Leu Pro Pro Gly Cys Gly Asp
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Pro Lys Arg Leu Gly Pro Leu Arg Gly Phe Gln Trp Val Thr Gly Asp
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Asn Asn Thr Ser Tyr Ser Arg Trp Ala Arg Leu Asp Leu Asn Gly Ala
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Pro Leu Cys Gly Pro Leu Cys Val Ala Val Ser Ala Ala Glu Ala Thr
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Val Pro Ser Glu Pro Ile Trp Glu Glu Gln Gln Cys Glu Val Lys Ala
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Asp Gly Phe Leu Cys Glu Phe His Phe Pro Ala Thr Cys Arg Pro Leu
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Ala Val Glu Pro Gly Ala Ala Ala Ala Ala Val Ser Ile Thr Tyr Gly
165 170 175
Thr Pro Phe Ala Ala Arg Gly Ala Asp Phe Gln Ala Leu Pro Val Gly
180 185 190
Ser Ser Ala Ala Val Ala Pro Leu Gly Leu Gln Leu Met Cys Thr Ala
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Pro Pro Gly Ala Val Gln Gly His Trp Ala Arg Glu Ala Pro Gly Ala
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Trp Asp Cys Ser Val Glu Asn Gly Gly Cys Glu His Ala Cys Asn Ala
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Ile Pro Gly Ala Pro Arg Cys Gln Cys Pro Ala Gly Ala Ala Leu Gln
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Ala Asp Gly Arg Ser Cys Thr Ala Ser Ala Thr Gln Ser Cys Asn Asp
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Leu Cys Glu His Phe Cys Val Pro Asn Pro Asp Gln Pro Gly Ser Tyr
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Ser Cys Met Cys Glu Thr Gly Tyr Arg Leu Ala Ala Asp Gln His Arg
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Cys Glu Asp Val Asp Asp Cys Ile Leu Glu Pro Ser Pro Cys Pro Gln
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Arg Cys Val Asn Thr Gln Gly Gly Phe Glu Cys His Cys Tyr Pro Asn
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Tyr Asp Leu Val Asp Gly Glu Cys Val Glu Pro Val Asp Pro Cys Phe
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Arg Ala Asn Cys Glu Tyr Gln Cys Gln Pro Leu Asn Gln Thr Ser Tyr
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Leu Cys Val Cys Ala Glu Gly Phe Ala Pro Ile Pro His Glu Pro His
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Arg Cys Gln Met Phe Cys Asn Gln Thr Ala Cys Pro Ala Asp Cys Asp
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Pro Asn Thr Gln Ala Ser Cys Glu Cys Pro Glu Gly Tyr Ile Leu Asp
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Asp Gly Phe Ile Cys Thr Asp Ile Asp Glu Cys Glu Asn Gly Gly Phe
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Cys Ser Gly Val Cys His Asn Leu Pro Gly Thr Phe Glu Cys Ile Cys
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Gly Pro Asp Ser Ala Leu Ala Arg His Ile Gly Thr Asp Cys Asp Ser
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Gly Lys Val Asp Gly Gly Asp Ser Gly Ser Gly Glu Pro Pro Pro Ser
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Pro Thr Pro Gly Ser Thr Leu Thr Pro Pro Ala Val Gly Leu Val His
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Ser Gly Leu Leu Ile Gly Ile Ser Ile Ala Ser Leu Cys Leu Val Val
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Ala Leu Leu Ala Leu Leu Cys His Leu Arg Lys Lys Gln Gly Ala Ala
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Arg Ala Lys Met Glu Tyr Lys Cys Ala Ala Pro Ser Lys Glu Val Val
530 535 540
Leu Gln His Val Arg Thr Glu Arg Thr Pro Gln Arg Leu
545 550 555
<210> 2
<211> 274
<212> PRT
<213> 智人(Homo sapiens)
<400> 2
Ala Trp Asp Cys Ser Val Glu Asn Gly Gly Cys Glu His Ala Cys Asn
1 5 10 15
Ala Ile Pro Gly Ala Pro Arg Cys Gln Cys Pro Ala Gly Ala Ala Leu
20 25 30
Gln Ala Asp Gly Arg Ser Cys Thr Ala Ser Ala Thr Gln Ser Cys Asn
35 40 45
Asp Leu Cys Glu His Phe Cys Val Pro Asn Pro Asp Gln Pro Gly Ser
50 55 60
Tyr Ser Cys Met Cys Glu Thr Gly Tyr Arg Leu Ala Ala Asp Gln His
65 70 75 80
Arg Cys Glu Asp Val Asp Asp Cys Ile Leu Glu Pro Ser Pro Cys Pro
85 90 95
Gln Arg Cys Val Asn Thr Gln Gly Gly Phe Glu Cys His Cys Tyr Pro
100 105 110
Asn Tyr Asp Leu Val Asp Gly Glu Cys Val Glu Pro Val Asp Pro Cys
115 120 125
Phe Arg Ala Asn Cys Glu Tyr Gln Cys Gln Pro Leu Asn Gln Thr Ser
130 135 140
Tyr Leu Cys Val Cys Ala Glu Gly Phe Ala Pro Ile Pro His Glu Pro
145 150 155 160
His Arg Cys Gln Met Phe Cys Asn Gln Thr Ala Cys Pro Ala Asp Cys
165 170 175
Asp Pro Asn Thr Gln Ala Ser Cys Glu Cys Pro Glu Gly Tyr Ile Leu
180 185 190
Asp Asp Gly Phe Ile Cys Thr Asp Ile Asp Glu Cys Glu Asn Gly Gly
195 200 205
Phe Cys Ser Gly Val Cys His Asn Leu Pro Gly Thr Phe Glu Cys Ile
210 215 220
Cys Gly Pro Asp Ser Ala Leu Ala Arg His Ile Gly Thr Asp Cys Asp
225 230 235 240
Ser Gly Lys Val Asp Gly Gly Asp Ser Gly Ser Gly Glu Pro Pro Pro
245 250 255
Ser Pro Thr Pro Gly Ser Thr Leu Thr Pro Pro Ala Val Gly Leu Val
260 265 270
His Ser
<210> 3
<211> 274
<212> PRT
<213> 智人(Homo sapiens)
<400> 3
Ala Trp Asp Cys Ser Val Glu Asn Gly Gly Cys Glu His Ala Cys Asn
1 5 10 15
Ala Ile Pro Gly Ala Pro Arg Cys Gln Cys Pro Ala Gly Ala Ala Leu
20 25 30
Gln Ala Asp Gly Arg Ser Cys Thr Ala Ser Ala Thr Gln Ser Cys Asn
35 40 45
Asp Leu Cys Glu His Phe Cys Val Pro Asn Pro Asp Gln Pro Gly Ser
50 55 60
Tyr Ser Cys Met Cys Glu Thr Gly Tyr Arg Leu Ala Ala Asp Gln His
65 70 75 80
Arg Cys Glu Asp Val Asp Asp Cys Ile Leu Glu Pro Ser Pro Cys Pro
85 90 95
Gln Arg Cys Val Asn Thr Gln Gly Gly Phe Glu Cys His Cys Tyr Pro
100 105 110
Asn Tyr Asp Leu Val Asp Gly Glu Cys Val Glu Pro Val Asp Pro Cys
115 120 125
Phe Arg Ala Asn Cys Glu Tyr Gln Cys Gln Pro Leu Ala Gln Thr Ser
130 135 140
Tyr Leu Cys Val Cys Ala Glu Gly Phe Ala Pro Ile Pro His Glu Pro
145 150 155 160
His Arg Cys Gln Met Phe Cys Ala Gln Thr Ala Cys Pro Ala Asp Cys
165 170 175
Asp Pro Asn Thr Gln Ala Ser Cys Glu Cys Pro Glu Gly Tyr Ile Leu
180 185 190
Asp Asp Gly Phe Ile Cys Thr Asp Ile Asp Glu Cys Glu Asn Gly Gly
195 200 205
Phe Cys Ser Gly Val Cys His Asn Leu Pro Gly Thr Phe Glu Cys Ile
210 215 220
Cys Gly Pro Asp Ser Ala Leu Ala Arg His Ile Gly Thr Asp Cys Asp
225 230 235 240
Ser Gly Lys Val Asp Gly Gly Asp Ser Gly Ser Gly Glu Pro Pro Pro
245 250 255
Ser Pro Thr Pro Gly Ser Thr Leu Thr Pro Pro Ala Val Gly Leu Val
260 265 270
His Ser
<210> 4
<211> 497
<212> PRT
<213> 智人(Homo sapiens)
<400> 4
Ala Pro Ala Glu Pro Gln Pro Gly Gly Ser Gln Cys Val Glu His Asp
1 5 10 15
Cys Phe Ala Leu Tyr Pro Gly Pro Ala Thr Phe Leu Asn Ala Ser Gln
20 25 30
Ile Cys Asp Gly Leu Arg Gly His Leu Met Thr Val Arg Ser Ser Val
35 40 45
Ala Ala Asp Val Ile Ser Leu Leu Leu Asn Gly Asp Gly Gly Val Gly
50 55 60
Arg Arg Arg Leu Trp Ile Gly Leu Gln Leu Pro Pro Gly Cys Gly Asp
65 70 75 80
Pro Lys Arg Leu Gly Pro Leu Arg Gly Phe Gln Trp Val Thr Gly Asp
85 90 95
Asn Asn Thr Ser Tyr Ser Arg Trp Ala Arg Leu Asp Leu Asn Gly Ala
100 105 110
Pro Leu Cys Gly Pro Leu Cys Val Ala Val Ser Ala Ala Glu Ala Thr
115 120 125
Val Pro Ser Glu Pro Ile Trp Glu Glu Gln Gln Cys Glu Val Lys Ala
130 135 140
Asp Gly Phe Leu Cys Glu Phe His Phe Pro Ala Thr Cys Arg Pro Leu
145 150 155 160
Ala Val Glu Pro Gly Ala Ala Ala Ala Ala Val Ser Ile Thr Tyr Gly
165 170 175
Thr Pro Phe Ala Ala Arg Gly Ala Asp Phe Gln Ala Leu Pro Val Gly
180 185 190
Ser Ser Ala Ala Val Ala Pro Leu Gly Leu Gln Leu Met Cys Thr Ala
195 200 205
Pro Pro Gly Ala Val Gln Gly His Trp Ala Arg Glu Ala Pro Gly Ala
210 215 220
Trp Asp Cys Ser Val Glu Asn Gly Gly Cys Glu His Ala Cys Asn Ala
225 230 235 240
Ile Pro Gly Ala Pro Arg Cys Gln Cys Pro Ala Gly Ala Ala Leu Gln
245 250 255
Ala Asp Gly Arg Ser Cys Thr Ala Ser Ala Thr Gln Ser Cys Asn Asp
260 265 270
Leu Cys Glu His Phe Cys Val Pro Asn Pro Asp Gln Pro Gly Ser Tyr
275 280 285
Ser Cys Met Cys Glu Thr Gly Tyr Arg Leu Ala Ala Asp Gln His Arg
290 295 300
Cys Glu Asp Val Asp Asp Cys Ile Leu Glu Pro Ser Pro Cys Pro Gln
305 310 315 320
Arg Cys Val Asn Thr Gln Gly Gly Phe Glu Cys His Cys Tyr Pro Asn
325 330 335
Tyr Asp Leu Val Asp Gly Glu Cys Val Glu Pro Val Asp Pro Cys Phe
340 345 350
Arg Ala Asn Cys Glu Tyr Gln Cys Gln Pro Leu Asn Gln Thr Ser Tyr
355 360 365
Leu Cys Val Cys Ala Glu Gly Phe Ala Pro Ile Pro His Glu Pro His
370 375 380
Arg Cys Gln Met Phe Cys Asn Gln Thr Ala Cys Pro Ala Asp Cys Asp
385 390 395 400
Pro Asn Thr Gln Ala Ser Cys Glu Cys Pro Glu Gly Tyr Ile Leu Asp
405 410 415
Asp Gly Phe Ile Cys Thr Asp Ile Asp Glu Cys Glu Asn Gly Gly Phe
420 425 430
Cys Ser Gly Val Cys His Asn Leu Pro Gly Thr Phe Glu Cys Ile Cys
435 440 445
Gly Pro Asp Ser Ala Leu Ala Arg His Ile Gly Thr Asp Cys Asp Ser
450 455 460
Gly Lys Val Asp Gly Gly Asp Ser Gly Ser Gly Glu Pro Pro Pro Ser
465 470 475 480
Pro Thr Pro Gly Ser Thr Leu Thr Pro Pro Ala Val Gly Leu Val His
485 490 495
Ser
<210> 5
<211> 497
<212> PRT
<213> 智人(Homo sapiens)
<400> 5
Ala Pro Ala Glu Pro Gln Pro Gly Gly Ser Gln Cys Val Glu His Asp
1 5 10 15
Cys Phe Ala Leu Tyr Pro Gly Pro Ala Thr Phe Leu Asn Ala Ser Gln
20 25 30
Ile Cys Asp Gly Leu Arg Gly His Leu Met Thr Val Arg Ser Ser Val
35 40 45
Ala Ala Asp Val Ile Ser Leu Leu Leu Asn Gly Asp Gly Gly Val Gly
50 55 60
Arg Arg Arg Leu Trp Ile Gly Leu Gln Leu Pro Pro Gly Cys Gly Asp
65 70 75 80
Pro Lys Arg Leu Gly Pro Leu Arg Gly Phe Gln Trp Val Thr Gly Asp
85 90 95
Asn Asn Thr Ser Tyr Ser Arg Trp Ala Arg Leu Asp Leu Asn Gly Ala
100 105 110
Pro Leu Cys Gly Pro Leu Cys Val Ala Val Ser Ala Ala Glu Ala Thr
115 120 125
Val Pro Ser Glu Pro Ile Trp Glu Glu Gln Gln Cys Glu Val Lys Ala
130 135 140
Asp Gly Phe Leu Cys Glu Phe His Phe Pro Ala Thr Cys Arg Pro Leu
145 150 155 160
Ala Val Glu Pro Gly Ala Ala Ala Ala Ala Val Ser Ile Thr Tyr Gly
165 170 175
Thr Pro Phe Ala Ala Arg Gly Ala Asp Phe Gln Ala Leu Pro Val Gly
180 185 190
Ser Ser Ala Ala Val Ala Pro Leu Gly Leu Gln Leu Met Cys Thr Ala
195 200 205
Pro Pro Gly Ala Val Gln Gly His Trp Ala Arg Glu Ala Pro Gly Ala
210 215 220
Trp Asp Cys Ser Val Glu Asn Gly Gly Cys Glu His Ala Cys Asn Ala
225 230 235 240
Ile Pro Gly Ala Pro Arg Cys Gln Cys Pro Ala Gly Ala Ala Leu Gln
245 250 255
Ala Asp Gly Arg Ser Cys Thr Ala Ser Ala Thr Gln Ser Cys Asn Asp
260 265 270
Leu Cys Glu His Phe Cys Val Pro Asn Pro Asp Gln Pro Gly Ser Tyr
275 280 285
Ser Cys Met Cys Glu Thr Gly Tyr Arg Leu Ala Ala Asp Gln His Arg
290 295 300
Cys Glu Asp Val Asp Asp Cys Ile Leu Glu Pro Ser Pro Cys Pro Gln
305 310 315 320
Arg Cys Val Asn Thr Gln Gly Gly Phe Glu Cys His Cys Tyr Pro Asn
325 330 335
Tyr Asp Leu Val Asp Gly Glu Cys Val Glu Pro Val Asp Pro Cys Phe
340 345 350
Arg Ala Asn Cys Glu Tyr Gln Cys Gln Pro Leu Ala Gln Thr Ser Tyr
355 360 365
Leu Cys Val Cys Ala Glu Gly Phe Ala Pro Ile Pro His Glu Pro His
370 375 380
Arg Cys Gln Met Phe Cys Ala Gln Thr Ala Cys Pro Ala Asp Cys Asp
385 390 395 400
Pro Asn Thr Gln Ala Ser Cys Glu Cys Pro Glu Gly Tyr Ile Leu Asp
405 410 415
Asp Gly Phe Ile Cys Thr Asp Ile Asp Glu Cys Glu Asn Gly Gly Phe
420 425 430
Cys Ser Gly Val Cys His Asn Leu Pro Gly Thr Phe Glu Cys Ile Cys
435 440 445
Gly Pro Asp Ser Ala Leu Ala Arg His Ile Gly Thr Asp Cys Asp Ser
450 455 460
Gly Lys Val Asp Gly Gly Asp Ser Gly Ser Gly Glu Pro Pro Pro Ser
465 470 475 480
Pro Thr Pro Gly Ser Thr Leu Thr Pro Pro Ala Val Gly Leu Val His
485 490 495
Ser
Claims (17)
1.包含与人血栓调节蛋白结构域2和3(TMD23)具有至少80％同一性的氨基酸序列的生物活性重组多肽在制备用于在有需要的受试者中刺激骨再生、骨增强，治疗骨丢失、骨病症和/或骨相关病症的药物中的用途，其中所述多肽不含或缺乏来自人血栓调节蛋白结构域4和5的氨基酸残基。
2.包含重组的人血栓调节蛋白结构域2和3(rTMD23)的分离多肽或其生物活性重组变体在制备用于在有需要的受试者中刺激骨再生、骨增强，治疗骨丢失、骨病症和/或骨相关病症的药物中的用途，其中，所述其生物活性变体包含与人血栓调节蛋白结构域2和3(TMD23)具有至少80％同一性的氨基酸序列，并且进一步地，其中所述多肽不含或缺乏来自人血栓调节蛋白结构域4和5的氨基酸残基。
3.如权利要求1或2所述的用途，其中，所述多肽包含来自人血栓调节蛋白结构域2和3的氨基酸残基。
4.如权利要求1或2所述的用途，其中，所述多肽包含SEQ ID NO:1的224Ala至497Ser或1Ala至497Ser的氨基酸残基。
5.如权利要求1或2所述的用途，其中，所述多肽包含SEQ ID NO:3的氨基酸序列。
6.如权利要求1所述的用途，其中，所述多肽是生物活性重组TMD23变体且包含SEQ IDNO:3的氨基酸序列。
7.如权利要求1至6中任一项所述的用途，其中，所述多肽进一步包含来自人血栓调节蛋白结构域1的氨基酸残基。
8.如权利要求2或6所述的用途，其中，所述重组TMD23变体由SEQ ID NO:3的氨基酸序列组成。
9.如权利要求1或2中任一项所述的用途，其中，所述多肽包含选自SEQ ID NO:2、SEQID NO:3、SEQ ID NO:4和SEQ ID NO:5的氨基酸序列。
10.如权利要求1或2所述的用途，其中，所述多肽或所述生物活性变体包含与rTMD23具有至少95％同一性的氨基酸序列。
11.如权利要求1或2所述的用途，其中，所述多肽或所述生物活性变体包含与rTMD23具有至少90％同一性的氨基酸残基。
12.重组的人血栓调节蛋白结构域2和3(rTMD23)或其生物活性重组变体在制备用于在有需要的受试者中刺激骨再生、骨增强，治疗骨丢失、骨病症和/或骨相关病症的药物中的用途，其中，所述其生物活性变体包含与人血栓调节蛋白结构域2和3具有至少80％同一性的氨基酸序列。
13.如权利要求12所述的用途，其中，rTMD23的重组变体包含SEQ ID NO:3的氨基酸序列。
14.如权利要求1、2或12所述的用途，其中，所述骨病症是一种疾病或症状，其选自骨质疏松症、骨丢失、未能实现最佳骨形成、未能实现最佳骨折愈合、骨骼生长期间达到低峰值骨量以及受损的新骨形成中的至少一种。
15.如权利要求1、2或12所述的用途，其中，所述骨相关病症是选自甲状旁腺机能亢进症、甲状旁腺机能亢进症相关骨量减少症、甲状旁腺机能亢进症相关骨量密度减少症、骨质减少症、骨丢失、炎性骨丢失、骨质疏松症、老年骨质疏松症、绝经后骨质疏松症、糖皮质激素诱导的骨质疏松症、颌骨骨坏死、佩吉特病和高磷血症中的至少一种。
16.如权利要求1、2或12所述的用途，其与骨移植材料结合用于制造用于刺激新骨形成的药物。
17.如权利要求1或2所述的用途，其中，所述多肽或所述生物活性变体包含与rTMD23具有至少85％同一性的氨基酸残基。
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| US201962951490P | 2019-12-20 | 2019-12-20 | |
| US62/951,490 | 2019-12-20 | ||
| PCT/US2020/065064 WO2021126822A1 (en) | 2019-12-20 | 2020-12-15 | Thrombomodulin functional domains for use in promoting osteoblast functions and bone healing |
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| US (1) | US20230000955A1 (zh) |
| EP (1) | EP4076491A4 (zh) |
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| US20170216407A1 (en) * | 2016-01-29 | 2017-08-03 | Kaohsiung Medical University | Tmd1 protein for treating bone loss diseases |
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| US9061000B2 (en) * | 2012-01-19 | 2015-06-23 | Chao-Han LAI | Pharmacological treatment of aortic aneurysm development |
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| US9156904B2 (en) * | 2013-07-29 | 2015-10-13 | Blue Blood Biotech Corp. | Thrombomodulin variants and use thereof |
| US9730983B2 (en) * | 2015-10-02 | 2017-08-15 | Chih-Yuan MA | Methods for treatment of CD14-mediated disorders and responses |
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- 2020-12-15 EP EP20900844.0A patent/EP4076491A4/en active Pending
- 2020-12-15 WO PCT/US2020/065064 patent/WO2021126822A1/en unknown
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| JPH08301783A (ja) * | 1995-05-11 | 1996-11-19 | Mochida Pharmaceut Co Ltd | 吸収性骨疾患予防・治療剤 |
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| Publication number | Publication date |
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| EP4076491A4 (en) | 2024-02-07 |
| US20230000955A1 (en) | 2023-01-05 |
| WO2021126822A1 (en) | 2021-06-24 |
| EP4076491A1 (en) | 2022-10-26 |
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