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通讯作者:

陈克明(1968-),男,甘肃兰州人,硕士生导师,主要从事骨科基础研究。E-mail:chenkm@lut.cn

中图分类号:R681,R459.9

文献标识码:A

文章编号:2096-8965(2021)04-0075-05

DOI:10.12287/j.issn.2096-8965.20210410

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目录contents

    摘要

    骨质疏松症被定义为一种系统性骨骼疾病,其特征是骨量低、骨组织微结构恶化、骨脆性和骨折易感性增加。 目前有2亿多人患有骨质疏松症,但由于人口老龄化和人均寿命延长,受影响的人数仍在急剧增加,这是一个重大的公共卫生问题。目前,治疗骨质疏松症的药物开发已经取得了重大进展,但药物治疗并不能逆转骨丢失,且会给患者带来一系列毒副作用。大量研究表明,骨髓间充质干细胞的归巢作用、成骨分化和细胞因子作用在骨质疏松发病过程中发挥重要作用。 移植骨髓间充质干细胞作为一种新方法,不仅能避开药物治疗的副作用而且能从根本上治疗骨质疏松,具有巨大的潜能和应用价值,但许多问题也有待解决。

    Abstract

    Osteoporosis is defined as a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Nowadays more than 200 million individuals are suffering from osteoporosis and still the number of affected people is dramatically increasing due to an aging population and longer life, representing a major public health problem. At present, great progress has been made in the development of drugs for the treatment of osteoporosis, but drug treatment can not reverse bone loss, and will bring a series of toxic and side effects to patients. A large number of studies have shown that homing disorders, osteogenic differentiation and cytokine effect of bone marrow mesenchymal stem cells play an important role in the pathogenesis of osteoporosis. As a new method, transplantation of bone marrow mesenchymal stem cells can not only avoid the side effects of drug therapy, but also fundamentally treat osteoporosis. It has great potential and application value, but there are also many problems to be solved.

  • 骨质疏松症 (Osteoporosis,OP) 是一种以骨量低和骨微结构恶化为特征的系统性骨骼疾病,大大增高了患者脆骨性骨折的风险,OP引起的骨折也是老年人发病和死亡的主要原因之一[1]。随着人口老龄化的加快,骨质疏松症日益普遍[2],对公共卫生保健提出了挑战。目前,骨质疏松的治疗以口服促骨形成或抗骨吸收药物为主,如双膦酸盐、降钙素等[3]。但传统的药物治疗并不能逆转患者的骨丢失现状,且会给患者带来严重的毒副作用如颌骨骨坏死、癌症、血栓栓塞、增加中风风险等,因此迫切需要寻找更为安全的新疗法[4]

  • 骨髓间充质干细胞 (Bone Marrow Mesenchymal Stem Cells,BMSCs) 于1976年由Friedenstein等[5] 首次从骨髓中分离并命名。BMSCs主要来源于骨髓,是一种具有自我更新和多谱系分化潜能的多能成纤维细胞[6],存在于骨髓、脐带血、胎盘、脂肪组织等多种组织中,可诱导分化为成骨细胞、软骨细胞、脂肪细胞,甚至内皮细胞或肝细胞等[7]。BMSCs易从成体组织中分离且具有广泛的增殖和分化成各种细胞谱系的能力,被认为是目前研究最多的一种再生细胞类型[8]。近些年来,BMSCs在治疗OP方面的潜能也逐渐被挖掘,BMSCs的归巢作用、成骨分化和细胞因子作用均与OP的进展密切相关。本文就BMSCs与OP的发生间的联系、移植BMSCs治疗OP的方法以及目前存在的问题作一综述,为后续研究提供一定的理论依据。

  • 1 BMSCs与OP的发生

  • 1.1 BMSCs的归巢作用

  • 众所周知,BMSCs从原来的微环境迁入外周血并随外周血循环到达损伤处,发挥局部功能和修复作用,这称为BMSCs的归巢作用,也是骨修复的起始步骤[9]。首先,BMSCs在外界刺激下进入外周血循环,多种细胞因子共同作用使BMSCs发生卷曲形变并与血管内皮细胞接触。附着在内皮细胞上的BMSCs与G蛋白偶联受体相结合,随后与整和素受体相结合,激活后的BMSCs穿过内皮细胞到达基底膜,在损伤部位通过软骨内骨化和膜内骨化参与骨形成过程[10]

  • Wang等[11] 提出,人体的衰老破坏了体内代谢系统,使BMSCs进入自我更新能力受损和分化能力异常的衰老状态,此时BMSCs的归巢功能受损,很难保证足够的间充质干细胞能够到达受损组织,从而阻碍了骨修复,增加了老年人群OP的发生率; Sanghani等[12] 发现,大鼠BMSCs迁移因年龄和骨质疏松而受损,这可能与骨质疏松患者骨形成的显著减少有关,提示了OP会破坏BMSCs的归巢功能从而大大减少了骨形成,但上调CXCR4水平可以改善干细胞的迁移,这可能会提高OP患者的骨质量; 有研究显示,BMSCs外泌体通过支持血管系统促进新骨形成,并显示出改善形态学、生物力学和组织学的结果,对细胞存活、增殖和迁移、成骨和血管生成具有积极作用[8]。为了让BMSCs正常发挥其归巢功能,也可通过BMSCs移植来增加BMSCs的总数,或通过基因修饰增强BMSCs的归巢。

  • 1.2 BMSCs的成骨分化

  • BMSCs向各种类型骨相关细胞的分化和成熟是由多种转录因子和信号通路决定的。BMSCs的分化平衡失调与多种病理生理状况有关,比如肥胖和OP[13]。成骨细胞和脂肪细胞有着共同的祖细胞BMSCs,转录因子RUNX2和过氧化物酶体增殖物激活受体 γ (Peroxisome Proliferators-Activated Receptors γ,PPARγ) 分别是成骨细胞和脂肪细胞生成的主要蛋白质,并在早期BMSCs的分化中起到关键作用[14]。BMP2被确定为同一系统内软骨分化、成骨分化和软骨内骨形成的调节因子,可通过表达RUNX2、 OSX (Osterix) 及其下游标记物,诱导BMSCs的成骨性分化和软骨内成骨[15]

  • OP的核心特征是成骨性分化减少和骨吸收增加[16]。Gurpreet等[17] 提出随着年龄的增长,BMSCs数量保持不变,而成熟成骨细胞数量减少,提示MSCs的成骨分化能力随着时间的推移而受损,导致骨微结构损伤及骨丢失;Xun等[18] 发现老年OP大鼠的BMSCs成骨分化明显降低,骨生成速度减缓; Wang等[19] 的研究中,OVX大鼠的BMSCs与假手术组大鼠的BMSCs相比,其成骨基因的表达明显降低,提示了OVX大鼠的BMSCs更差的增殖能力和更弱的成骨分化能力。因此,移植具有较好成骨分化能力的BMSCs对OP患者而言也是一种可供选择的方法。

  • 1.3 BMSCs分泌细胞因子

  • 骨重建是通过一系列的同步事件发生的,各种类型的细胞在微环境中被激活,破骨细胞的骨吸收作用和成骨细胞的骨形成作用同时进行,且成骨细胞和破骨细胞通过细胞间直接接触或分泌蛋白相互沟通,调节细胞行为、生存和分化,使骨组织维持平衡的功能状态[20]

  • 在微环境中,由细胞因子和趋化因子在内的分泌体介导的旁分泌作用有利于维持骨代谢的平衡状态[21]

  • Yang等[22] 发现BMSCs的外泌体MALAT1可通过上调SATB2的表达来增强OP小鼠的成骨细胞活性,提示了外泌体MALAT1在OVX小鼠模型中缓解骨质疏松症状的潜力;Takeuchi等[23] 采用了大鼠颅骨骨缺损模型,发现BMSCs所含的外泌体在早期促进了骨再生并促进血管生成,证明BMSCs所含的外泌体可能通过促进血管生成在骨再生中发挥重要作用,可作为骨再生的生物活性剂;Qiu等[24] 对OVX大鼠的体内外实验表明,BMSCs的外泌体miR-150-3p能促进成骨细胞增殖和分化,为OP患者的治疗提供了新的线索。所以,有望通过外源性BMSCs移植,利用BMSCs分泌的细胞因子作为一种旁分泌调节剂来刺激成骨。

  • 2 移植BMSCs治疗OP的可行性

  • 2.1 直接移植BMSCs治疗OP

  • BMSCs已被广泛应用于治疗OP的基础研究,已有大量动物实验证实了直接移植BMSCs促进成骨、改善骨质疏松症状的作用。Yu等[25] 利用聚乳酸聚乙醇酸共聚物 (Polylactic/Poly Glycolic Acid, PLGA)/I型胶原蛋白 (Collagen Type I,CoI) 微球联合BMSCs作为注射支架用于去卵巢的OP雌性大鼠,发现PLGA/CoI微球联合BMSCs可促进大鼠骨小梁重建,显著提高大鼠骨密度,骨质量得到有效改善,表明骨破坏和丢失可在一定程度上得到逆转;Cao等[26] 以切除卵巢后的山羊为OP模型,采用带有多孔B-TCP的自体骨髓间充质干细胞作为复合移植修复长期雌激素缺乏的山羊股骨内髁缺损,显微CT图像和组织形态学分析显示,骨小梁体积、骨小梁数、骨小梁厚度和骨小梁体积比均增加,骨小梁间距明显减少,表明骨小梁微结构变形可得到一定程度的缓解,治疗后山羊的骨形成得到明显改善;Kiernan等[27] 使用微创外源性BMSCs系统注射到人类年龄相关性OP的小鼠模型中,发现长期植入可以防止骨形成能力和骨质量的下降,证明了系统性BMSCs移植可预防年龄相关性OP小鼠模型的功能性骨丢失。因此,直接移植BMSCs可能是预防和治疗雌激素缺乏和年龄相关性骨质疏松的一种可行的治疗方案,为后续临床研究提供了依据。

  • 2.2 基因修饰后的BMSCs移植治疗OP

  • 大量研究已表明,移植未经修饰的BMSCs具有刺激机体成骨的作用。为了提高移植BMSCs的成骨能力,在移植前将相关基因进行修饰后移植,期望以此来增强BMSCs移植治疗OP的效果。根据已有的研究,可大致分为以下几种策略:

  • 2.2.1 促进骨形成

  • 骨形态发生蛋白 (Bone Morphogenetic Protein, BMPs) 属于转化生长因子-β超家族,在骨稳态中发挥重要作用,其中BMP-2是第一个被表征的BMP并得到了广泛的研究[28]。Tsuda等[29] 的研究发现,被ADV-F/RGD感染的BMSCs细胞能产生更多的BMP-2,显示出更有效的骨再生能力,可能是骨再生的强大基因治疗工具;Turgeman等[30] 将编码BMP-2的重组腺病毒载体感染后的人BMSCs移植到小鼠体内,显著增强了小鼠的骨形成,说明人BMSCs可以有效地转导人BMP-2编码腺病毒载体,且移植后的BMSCs能大大提高机体的成骨潜能; 除BMP-2外,过表达BMP-6基因的BMSCs移植也能诱导骨再生。Pelled等[31] 从供体动物的骨髓中分离出BMSCs,然后通过非病毒技术 (核感染) 转染以过度表达BMP-6,再将这些细胞悬浮在纤维蛋白凝胶中,并移植到一头猪的脊椎缺损处,结果显示移植组相比于对照组骨形成有明显增强。

  • 2.2.2 抑制骨吸收

  • 除修饰骨形成相关基因外,通过基因修饰来抑制破骨细胞的骨吸收作用也是一种可行的方法。 RANKL-RANK信号在破骨细胞骨吸收的调节中起着关键作用,RANKL和RANK结合能激活破骨前体细胞向成熟的破骨细胞增殖分化,抑制RANKL-RANK信号已成为骨质疏松症治疗的重要靶点[32]。 RANK Fc是RANKL的拮抗剂,可与RANKL结合来减少破骨细胞前体的激活,从而抑制骨吸收。Kim等[33] 的实验表明,在C57Bl/6小鼠中,经基因修饰的间充质干细胞在腹腔注射后能够持续分泌RANK-Fc长达8周,可有效抑制破骨细胞的激活,预防卵巢切除术所带来的骨丢失。

  • 2.2.3 加强BMSCs归巢

  • 研究表明SDF-1/CXCR4信号在促进BMSCs归巢中起重要作用,CXCR4是BMSCs归巢的关键信号分子[34]。Chen等[35] 将过表达CXCR4的BMSCs注入骨髓衰竭小鼠后,BMSCs的归巢作用显著加强,小鼠的造血功能得到明显提高;Sanghani等[36] 比较了年轻大鼠、移植经CXCR4修饰后的BMSCs的去卵巢大鼠以及直接移植BMSCs的去卵巢大鼠的骨形成情况,12周后的Micro CT和生物力学检测的结果显示,静脉注射CXCR4转染的BMSCs可以迁移到骨髓有效减少骨质疏松大鼠的骨丢失,并改善骨形成;Deng等[37] 发现SDF-1诱导CXCR4表达的BMSCs移植可促进大鼠创伤性脑损伤 (Traumatic Brain Injury, TBI) 的修复。

  • 3 目前存在的问题

  • 参考前期的动物实验结果,尽管自体BMSCs移植和异体BMSCs移植在理论上都是可行的,但异体BMSCs移植所带来的免疫排斥反应不可忽略[38]。因此,为避免此类风险,目前所进行的临床试验都采取了自体移植的方式。近些年来,在已有基础研究的基础上,自体BMSCs移植的临床实验正在逐步开展,但从基础实验到临床实验的转化仍存在一些困难和障碍需要去解决。

  • BMSCs移植真的安全吗?间充质干细胞因其自我更新能力带有肿瘤形成的固有风险[39],已有动物实验证明BMSCs移植增加了肿瘤转移的发生率和数量[40],同种异体脂肪来源间充质干细胞移植也可能会带来血栓等副作用[41];BMSCs移植的效率又如何呢?大多数间充质干细胞在静脉输注后会被困在肺内,这种肺首过效应降低了移植效率[42],此外,培养24小时的原代间充质干细胞移植后,其归巢能力降低到10%,而培养48小时的原代间充质干细胞移植后,靶器官内未检测到细胞[43];BMSCs移植的标准化治疗过程该如何被定义呢?Agata等[44] 报道骨髓内注射MSCs相比于静脉注射MSCs其安全性和有效性更高,究竟何种方式是最佳选择?不同组织来源的间充质干细胞各有优缺点,其性能和免疫原性各不相同,那么BMSCs的最佳来源是哪里? 这一系列的问题都需要研究者的进一步探索。

  • 4 总结与展望

  • OP不仅严重影响了患者的生活质量,也给社会带来了沉重的负担[45]。当前的药物疗法并不能从根本上逆转OP患者的骨丢失,且会给患者带来一系列的副作用。BMSCs作为一种具有分化潜能的干细胞,在骨稳态中起着重要的作用。已有大量动物实验证明,BMSCs移植能从本质上改变低骨质量的现状,促进骨形成的同时提高骨质量,在治疗OP方面潜力无穷。近年来,BMSCs移植治疗OP的临床实验正在进行,正逐步填补临床数据的空白,西班牙圣母玛利亚医院在2020年完成了静脉输注岩藻糖基化骨髓间充质细胞治疗骨质疏松症的临床试验(ClinicalTrials.gov Identifier: NCT02566655)。从基础研究向临床治疗的转化上,也存在着许多的困难和挑战,仍需要科研人员的不懈努力来解决这些难题,需要大量临床实验来将这项技术逐渐成熟与完善。

  • 参考文献

    • [1] COMPSTON J E,MCCLUNG M R,LESLIE W D.Osteoporosis[J].Lancet,2019,393(10169):364-376.

    • [2] NISHIZAWA Y,MIURA M,ICHIMURA S,et al.Executive summary of the Japan osteoporosis society guide for the use of bone turnover markers in the diagnosis and treatment of osteoporosis(2018 Edition)[J].Clin Chim Acta,2019,498:101-107.

    • [3] LANGDAHL B L.Overview of treatment approaches to osteoporosis[J].Br J Pharmacol,2021,178(9):1891-1906.

    • [4] LI H X,XIAO Z S,QUAILES L D,et al.Osteoporosis:mechanism,molecular target and current status on drug development[J].Curr Med Chem,2021,28(8):1489-1507.

    • [5] FIEDENSTEIN A J.Precursor cells of mechanocytes[J].Int Rev Cytol,1976,47:327-359.

    • [6] LIU S Y,XU X,LIANG S J,et al.The application of MSCs-derived extracellular vesicles in bone disorders:novel cell-free therapeutic strategy[J].Front Cell Dev Biol,2020,8:619.

    • [7] MUSHAHARY D,SPITTLER A,KASPER C,et al.Isolation,cultivation,and characterization of human mesenchymal stem cells[J].Cytometry A,2018,93(1):19-31.

    • [8] TAN S H S,WONG J R Y,SIM S J Y,et al.Mesenchymal stem cell exosomes in bone regenerative strategies-a systematic review of preclinical studies[J].Mater Today Bio,2020,7:100067.

    • [9] LIU H,LI D,ZHANG Y,et al.Inflammation,mesenchymal stem cells and bone regeneration[J].Histochem Cell Biol,2018,149(4):393-404.

    • [10] SU P,TIAN Y,YANG C,et al.Mesenchymal stem cell migration during bone formation and bone diseases therapy[J].Int J Mol Sci,2018,19(8):2343.

    • [11] WANG R X,WANG Y,ZHU L S,et al.Epigenetic regulation in mesenchymal stem cell aging and differentiation and osteoporosis[J].Stem Cells Int,2020,2020:8836258.

    • [12] SANGHANI-KERAI A,COATHUP M,SAMAZIDEH S,et al.Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4[J].Bone Joint Res,2017,6(6):358-365.

    • [13] PARK J W,FU S,HUANG B,et al.Alternative splicing in mesenchymal stem cell differentiation[J].Stem Cells,2020,38(10):1229-1240.

    • [14] CHEN Q,SHOU P,ZHENG C,et al.Fate decision of mesenchymal stem cells:adipocytes or osteoblasts[J].Cell Death Differ,2016,23(7):1128-1139.

    • [15] ZHOU N,LI Q,LIN X,et al.BMP2 induces chondrogenic differentiation,osteogenic differentiation and endochondral ossification in stem cells[J].Cell Tissue Res,2016,366(1):101-111.

    • [16] DE NIGRIS F,RUOSI C,COLELLA G,et al.Epigenetic therapies of osteoporosis[J].Bone,2021,142:115680.

    • [17] GURPREET S B,SILKSTONE D,VI L,et al.Exposure to a youthful circulaton rejuvenates bone repair through modulation of β-catenin[J].Nat Commun,2015,6:7131.

    • [18] XUN J Q,LI C,LIU M L,et al.Serum exosomes from young rats improve the reduced osteogenic differentiation of BMSCs in aged rats with osteoporosis after fatigue loading in vivo[J].Stem Cell Res Ther,2021,12(1):424.

    • [19] WANG Q,ZHAO B,LI C,et al.Decreased proliferation ability and differentiation potential of mesenchymal stem cells of osteoporosis rat[J].Asian Pac J Trop Med,2014,7(5):358-363.

    • [20] SALHOTRA A,SHAH H N,LEVI B,et al.Mechanisms of bone development and repair[J].Nat Rev Mol Cell Biol,2020,21(11):696-711.

    • [21] KIM J M,LIN C,STAVRE Z,et al.Osteoblast-osteoclast communication and bone homeostasis[J].Cells,2020,9(9):2073.

    • [22] YANG X C,YANG J X,LEI P F,et al.LncRNA MALAT1 shuttled by bone marrow-derived mesenchymal stem cells-secreted exosomes alleviates osteoporosis through mediating microRNA-34c/SATB2 axis[J].Aging(Albany NY),2019,26,11(20):8777-8791.

    • [23] TAKEUCHI R,KATAGIRI W,ENDO S,et al.Exosomes from conditioned media of bone marrow-derived mesenchymal stem cells promote bone regeneration by enhancing angiogenesis[J].PLoS One,2019,14(11):e0225472.

    • [24] QIU M,ZHAI S H,FU Q,et al.Bone marrow mesenchymal stem cells-derived exosomal MicroRNA-150-3p promotes osteoblast proliferation and differentiation in osteoporosis[J].Hum Gene Ther,2021,32(13-14):717-729.

    • [25] YU Z K,ZHU T Y,LI C D,et al.Improvement of intertrochanteric bone quality in osteoporotic female rats after injection of polylactic acid-polyglycolic acid copolymer/collagen type I microspheres combined with bone mesenchymal stem cells[J].Int Orthop,2012,36(10):2163-2171.

    • [26] CAO L,LIU G W,GAN Y K,et al.The use of autologous enriched bone marrow MSCs to enhance osteoporotic bone defect repair in long-term estrogen deficient goats[J].Biomaterials,2012,33(20):5076-5084.

    • [27] KIERNAN J,HU S,GRYNPAS M D,et al.Systemic mesenchymal stromal cell transplantation prevents functional bone loss in a mouse model of age-related osteoporosis[J].Stem Cells Transl Med,2016,5(5):683-693.

    • [28] HALLORAN D,DURBANO H W,NOHE A.Bone morphogenetic protein-2 in development and bone homeostasis[J].J Dev Biol,2020,8(3):19.

    • [29] TSUDA H,WADA T,YAMASHITA T,et al.Enhanced osteoinduction by mesenchymal stem cells transfected with a fiber-mutant adenoviral BMP2 gene[J].J Gene Med,2005,7(10):1322-1334.

    • [30] TURGEMAN G,PITTMAN D D,MÜLLAR R,et al.Engineered human mesenchymal stem cells:a novel platform for skeletal cell mediated gene therapy[J].J Gene Med,2001,3(3):240-251.

    • [31] PELLDE G,SHEYN D,TAWACKOLI W,et al.BMP6-engineered MSCs induce vertebral bone repair in a pig model:a pilot study[J].Stem Cells Int,2016,2016:6530624.

    • [32] MATSUMOTO T,ENDO I.RANKL as a target for the treatment of osteoporosis[J].J Bone Miner Metab,2021,39(1):91-105.

    • [33] KIM D,CHO S W,HER S J,et al.Retrovirus-mediated gene transfer of receptor activator of nuclear factor-kappaB-Fc prevents bone loss in ovariectomized mice[J].Stem Cells,2006,24(7):1798-1805.

    • [34] XIU G H,LI X L,YIN Y Y,et al.SDF-1/CXCR4 augments the therapeutic effect of bone marrow mesenchymal stem cells in the treatment of lipopolysaccharide-induced liver injury by promoting their migration through PI3K/Akt signaling pathway[J].Cell Transplant,2020,29:1-12.

    • [35] CHEN L,LI Y,CHEN W,et al.Enhanced recruitment and hematopoietic reconstitution of bone marrow-derived mesenchymal stem cells in bone marrow failure by the SDF-1/CXCR4[J].J Tissue Eng Regen Med,2020,14(9):1250-1260.

    • [36] SANGHANI A,OSAGIE-CLOUARD L,SAMIZZADEH S,et al.CXCR4 has the potential to enhance bone formation in osteopenic rats[J].Tissue Eng Part A,2018,24(23-24):1775-1783.

    • [37] DENG Q J,XU X F,REN J.Effects of SDF-1/CXCR4 on the repair of traumatic brain injury in rats by mediating bone marrow derived mesenchymal stem cells [J].Cell Mol Neurobiol,2018,38(2):467-477.

    • [38] ANKRUM J A,ONG J F,KARP J M.Mesenchymal stem cells:immune evasive,not immune privileged[J].Nat Biotechnol,2014,32(3):252-260.

    • [39] LI J H,FAN W S,WANG M M,et al.Effects of mesenchymal stem cells on solid tumor metastasis in experimental cancer models:a systematic review and metaanalysis[J].J Transl Med,2018,16(1):113.

    • [40] RIDGE S M,SULLIVAN F J,GLYNN S A.Mesenchymal stem cells:key players in cancer progression[J].Mol Cancer,2017,16(1):31.

    • [41] ÁLVARO-GRACIA J M,JOVER J A,GARCÍAVICUÑA R,et al.Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis(Cx611):results of a multicentre,dose escalation,randomised,single-blind,placebo-controlled phase Ib/IIa clinical trial[J].Ann Rheum Dis,2017,76(1):196-202.

    • [42] FISCHER U M,HARTING M T,JIMENEZ F,et al.Pulmonary passage is a major obstacle for intravenous stem cell delivery:the pulmonary first-pass effect[J].Stem Cells Dev,2009,18(5):683-692.

    • [43] ROMBOUTS W J,PLOEMACHER R E.Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture[J].Leukemia,2003,17(1):160-170.

    • [44] AGATA H,SUMITA Y,HIDAKA T,et al.Intra-bone marrow administration of mesenchymal stem/stromal cells is a promising approach for treating osteoporosis[J].Stem Cells Int,2019,2019:4214281.

    • [45] 林通,罗文君,马菲菲,等.低频脉冲电磁场联合双膦酸盐和钙剂治疗老年骨质疏松症的临床研究[J].西北国防医学杂志,2020,41(4):230-233.

  • 参考文献

    • [1] COMPSTON J E,MCCLUNG M R,LESLIE W D.Osteoporosis[J].Lancet,2019,393(10169):364-376.

    • [2] NISHIZAWA Y,MIURA M,ICHIMURA S,et al.Executive summary of the Japan osteoporosis society guide for the use of bone turnover markers in the diagnosis and treatment of osteoporosis(2018 Edition)[J].Clin Chim Acta,2019,498:101-107.

    • [3] LANGDAHL B L.Overview of treatment approaches to osteoporosis[J].Br J Pharmacol,2021,178(9):1891-1906.

    • [4] LI H X,XIAO Z S,QUAILES L D,et al.Osteoporosis:mechanism,molecular target and current status on drug development[J].Curr Med Chem,2021,28(8):1489-1507.

    • [5] FIEDENSTEIN A J.Precursor cells of mechanocytes[J].Int Rev Cytol,1976,47:327-359.

    • [6] LIU S Y,XU X,LIANG S J,et al.The application of MSCs-derived extracellular vesicles in bone disorders:novel cell-free therapeutic strategy[J].Front Cell Dev Biol,2020,8:619.

    • [7] MUSHAHARY D,SPITTLER A,KASPER C,et al.Isolation,cultivation,and characterization of human mesenchymal stem cells[J].Cytometry A,2018,93(1):19-31.

    • [8] TAN S H S,WONG J R Y,SIM S J Y,et al.Mesenchymal stem cell exosomes in bone regenerative strategies-a systematic review of preclinical studies[J].Mater Today Bio,2020,7:100067.

    • [9] LIU H,LI D,ZHANG Y,et al.Inflammation,mesenchymal stem cells and bone regeneration[J].Histochem Cell Biol,2018,149(4):393-404.

    • [10] SU P,TIAN Y,YANG C,et al.Mesenchymal stem cell migration during bone formation and bone diseases therapy[J].Int J Mol Sci,2018,19(8):2343.

    • [11] WANG R X,WANG Y,ZHU L S,et al.Epigenetic regulation in mesenchymal stem cell aging and differentiation and osteoporosis[J].Stem Cells Int,2020,2020:8836258.

    • [12] SANGHANI-KERAI A,COATHUP M,SAMAZIDEH S,et al.Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4[J].Bone Joint Res,2017,6(6):358-365.

    • [13] PARK J W,FU S,HUANG B,et al.Alternative splicing in mesenchymal stem cell differentiation[J].Stem Cells,2020,38(10):1229-1240.

    • [14] CHEN Q,SHOU P,ZHENG C,et al.Fate decision of mesenchymal stem cells:adipocytes or osteoblasts[J].Cell Death Differ,2016,23(7):1128-1139.

    • [15] ZHOU N,LI Q,LIN X,et al.BMP2 induces chondrogenic differentiation,osteogenic differentiation and endochondral ossification in stem cells[J].Cell Tissue Res,2016,366(1):101-111.

    • [16] DE NIGRIS F,RUOSI C,COLELLA G,et al.Epigenetic therapies of osteoporosis[J].Bone,2021,142:115680.

    • [17] GURPREET S B,SILKSTONE D,VI L,et al.Exposure to a youthful circulaton rejuvenates bone repair through modulation of β-catenin[J].Nat Commun,2015,6:7131.

    • [18] XUN J Q,LI C,LIU M L,et al.Serum exosomes from young rats improve the reduced osteogenic differentiation of BMSCs in aged rats with osteoporosis after fatigue loading in vivo[J].Stem Cell Res Ther,2021,12(1):424.

    • [19] WANG Q,ZHAO B,LI C,et al.Decreased proliferation ability and differentiation potential of mesenchymal stem cells of osteoporosis rat[J].Asian Pac J Trop Med,2014,7(5):358-363.

    • [20] SALHOTRA A,SHAH H N,LEVI B,et al.Mechanisms of bone development and repair[J].Nat Rev Mol Cell Biol,2020,21(11):696-711.

    • [21] KIM J M,LIN C,STAVRE Z,et al.Osteoblast-osteoclast communication and bone homeostasis[J].Cells,2020,9(9):2073.

    • [22] YANG X C,YANG J X,LEI P F,et al.LncRNA MALAT1 shuttled by bone marrow-derived mesenchymal stem cells-secreted exosomes alleviates osteoporosis through mediating microRNA-34c/SATB2 axis[J].Aging(Albany NY),2019,26,11(20):8777-8791.

    • [23] TAKEUCHI R,KATAGIRI W,ENDO S,et al.Exosomes from conditioned media of bone marrow-derived mesenchymal stem cells promote bone regeneration by enhancing angiogenesis[J].PLoS One,2019,14(11):e0225472.

    • [24] QIU M,ZHAI S H,FU Q,et al.Bone marrow mesenchymal stem cells-derived exosomal MicroRNA-150-3p promotes osteoblast proliferation and differentiation in osteoporosis[J].Hum Gene Ther,2021,32(13-14):717-729.

    • [25] YU Z K,ZHU T Y,LI C D,et al.Improvement of intertrochanteric bone quality in osteoporotic female rats after injection of polylactic acid-polyglycolic acid copolymer/collagen type I microspheres combined with bone mesenchymal stem cells[J].Int Orthop,2012,36(10):2163-2171.

    • [26] CAO L,LIU G W,GAN Y K,et al.The use of autologous enriched bone marrow MSCs to enhance osteoporotic bone defect repair in long-term estrogen deficient goats[J].Biomaterials,2012,33(20):5076-5084.

    • [27] KIERNAN J,HU S,GRYNPAS M D,et al.Systemic mesenchymal stromal cell transplantation prevents functional bone loss in a mouse model of age-related osteoporosis[J].Stem Cells Transl Med,2016,5(5):683-693.

    • [28] HALLORAN D,DURBANO H W,NOHE A.Bone morphogenetic protein-2 in development and bone homeostasis[J].J Dev Biol,2020,8(3):19.

    • [29] TSUDA H,WADA T,YAMASHITA T,et al.Enhanced osteoinduction by mesenchymal stem cells transfected with a fiber-mutant adenoviral BMP2 gene[J].J Gene Med,2005,7(10):1322-1334.

    • [30] TURGEMAN G,PITTMAN D D,MÜLLAR R,et al.Engineered human mesenchymal stem cells:a novel platform for skeletal cell mediated gene therapy[J].J Gene Med,2001,3(3):240-251.

    • [31] PELLDE G,SHEYN D,TAWACKOLI W,et al.BMP6-engineered MSCs induce vertebral bone repair in a pig model:a pilot study[J].Stem Cells Int,2016,2016:6530624.

    • [32] MATSUMOTO T,ENDO I.RANKL as a target for the treatment of osteoporosis[J].J Bone Miner Metab,2021,39(1):91-105.

    • [33] KIM D,CHO S W,HER S J,et al.Retrovirus-mediated gene transfer of receptor activator of nuclear factor-kappaB-Fc prevents bone loss in ovariectomized mice[J].Stem Cells,2006,24(7):1798-1805.

    • [34] XIU G H,LI X L,YIN Y Y,et al.SDF-1/CXCR4 augments the therapeutic effect of bone marrow mesenchymal stem cells in the treatment of lipopolysaccharide-induced liver injury by promoting their migration through PI3K/Akt signaling pathway[J].Cell Transplant,2020,29:1-12.

    • [35] CHEN L,LI Y,CHEN W,et al.Enhanced recruitment and hematopoietic reconstitution of bone marrow-derived mesenchymal stem cells in bone marrow failure by the SDF-1/CXCR4[J].J Tissue Eng Regen Med,2020,14(9):1250-1260.

    • [36] SANGHANI A,OSAGIE-CLOUARD L,SAMIZZADEH S,et al.CXCR4 has the potential to enhance bone formation in osteopenic rats[J].Tissue Eng Part A,2018,24(23-24):1775-1783.

    • [37] DENG Q J,XU X F,REN J.Effects of SDF-1/CXCR4 on the repair of traumatic brain injury in rats by mediating bone marrow derived mesenchymal stem cells [J].Cell Mol Neurobiol,2018,38(2):467-477.

    • [38] ANKRUM J A,ONG J F,KARP J M.Mesenchymal stem cells:immune evasive,not immune privileged[J].Nat Biotechnol,2014,32(3):252-260.

    • [39] LI J H,FAN W S,WANG M M,et al.Effects of mesenchymal stem cells on solid tumor metastasis in experimental cancer models:a systematic review and metaanalysis[J].J Transl Med,2018,16(1):113.

    • [40] RIDGE S M,SULLIVAN F J,GLYNN S A.Mesenchymal stem cells:key players in cancer progression[J].Mol Cancer,2017,16(1):31.

    • [41] ÁLVARO-GRACIA J M,JOVER J A,GARCÍAVICUÑA R,et al.Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis(Cx611):results of a multicentre,dose escalation,randomised,single-blind,placebo-controlled phase Ib/IIa clinical trial[J].Ann Rheum Dis,2017,76(1):196-202.

    • [42] FISCHER U M,HARTING M T,JIMENEZ F,et al.Pulmonary passage is a major obstacle for intravenous stem cell delivery:the pulmonary first-pass effect[J].Stem Cells Dev,2009,18(5):683-692.

    • [43] ROMBOUTS W J,PLOEMACHER R E.Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture[J].Leukemia,2003,17(1):160-170.

    • [44] AGATA H,SUMITA Y,HIDAKA T,et al.Intra-bone marrow administration of mesenchymal stem/stromal cells is a promising approach for treating osteoporosis[J].Stem Cells Int,2019,2019:4214281.

    • [45] 林通,罗文君,马菲菲,等.低频脉冲电磁场联合双膦酸盐和钙剂治疗老年骨质疏松症的临床研究[J].西北国防医学杂志,2020,41(4):230-233.

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