骨质疏松症与内皮祖细胞相关性研究进展

刘志军，孔俊超，曾荣

(广东医科大学附属医院骨科，广东湛江524000)

骨质疏松症与内皮祖细胞相关性研究进展

刘志军，孔俊超，曾荣

(广东医科大学附属医院骨科，广东湛江524000)

内皮祖细胞是具有多方向分化的潜能的细胞亚群，可分化为血管内皮细胞和成骨细胞，参与血管形成及骨的再生，其在疾病研究的运用也相当广泛。成骨系细胞凋亡是糖皮质激素性骨质疏松发生的生物学基础，而骨-血管耦联概念的提出，提示骨组织的血管发生与骨发生存在密切的交叉对话。基于血管与成骨系细胞方面对骨质疏松的重要性，以及内皮细胞的分化能力和对组织的修复能力，该文对骨质疏松症与内皮祖细胞相关性作一综述。

骨质疏松症；内皮祖细胞；血管形成；成骨细胞

众所周知，骨质疏松是一种以骨量减少、骨微细结构破坏并多数伴有骨痛为特征的全身性代谢性骨病，按病因可分为原发性和继发性两类[1]。骨质疏松症患者骨组织内的成骨系细胞数目大量减少，骨骼脆性增加，在体质量或轻微损伤作用下，腰椎、股骨颈等负重骨易发生骨折[2]。原发性骨质疏松与衰老有关，随年龄增长而出现；继发性骨质疏松主要是由于药物治疗或一些疾病引起的并发症，糖皮质激素性骨质疏松(GIOP)是其中最常见的一种[3]。随着地塞米松(Dexamethasone，Dex)等外源性糖皮质激素(GC)在临床上应用需求的增加，GIOP的发病率呈现不断上升趋势[2]。

1 骨质疏松与成骨系细胞间的联系

目前临床上防治GIOP的主要策略是在确保患者摄取足量钙剂与维生素D的条件下，为其施用双膦酸盐类药物[4]。该方法借鉴了治疗原发性骨质疏松的临床用药原则，利用双膦酸盐可特异性聚集在破骨细胞表面并引起其凋亡的特点，抑制破骨细胞骨吸收功能，能一定程度上缓解机体骨量减少的症状，但却无法彻底阻断GIOP病程进展[5]。这种现象产生的一个主要原因在于GIOP和原发性骨质疏松截然不同的发病机制：原发性骨质疏松是由于骨内膜表面下破骨细胞功能增加所致，其特征是皮质骨变薄，骨代谢处于骨吸收大于骨形成的失衡状态[6]；而GIOP却主要是由于GC对成骨细胞活性的抑制作用所引发的，表现为松质骨的骨形成减少。以破骨细胞为作用靶点的双膦酸盐类药物由于不能增强成骨细胞活性，所以其阻断GIOP发展的作用并不显著[7]。由此亦可见，消除GC的骨形成抑制作用才是从根本上阻止GIOP进展的关键所在。骨重塑的过程中，破骨细胞的骨吸收与成骨细胞的骨形成间需要精准的平衡以保持骨的完整性[8]，在绝经后妇女中常发现的骨质疏松症则是骨吸收与骨形成两个过程不平衡导致[9]。病理学研究发现，GIOP骨组织内的BMMSCs、成骨细胞和骨细胞数明显减少，且下降程度与GC应用剂量呈正比，而与此同时，破骨细胞的数量却未出现显著变化，提示GC的骨形成抑制作用与成骨系细胞数目减少有直接联系[10]。

2 骨质疏松与血管的相关性

原发性或继发性骨质疏松的发生发展也和骨血流灌注障碍有密切关系。滋养长骨的血管主要有滋养动脉、干骺端动脉、骺动脉、骨膜动脉这些动脉进入骨髓腔后形成皮质骨和骨髓微循环[11]。骨小梁和哈佛氏管表面的骨内膜、皮质骨内的哈佛氏管以及维持正常骨生长都必须有血管生成的参与[12]，而血管的最重要组成部分之一是内皮细胞，内皮细胞不仅作为高渗透性的屏障也可分泌相关因子聚集如造血细胞促进骨生长[13-14]。研究发现，与骨骼生长有关的成骨细胞和血管生长间是有耦联关系的，这表明内皮细胞和成骨细胞间具有分子交换[15]。Burkhardt等[16]观察骨质疏松症的骨组织学样本发现与正常骨组织相比其单位面积内的窦状毛细血管和动脉毛细血管数量是减少的；Qiang等[17]报道了骨血管化的减少与雌激素缺失介导的骨缺失的相关性；Tatsuno等[18]发现GIOP可引起骨髓血管减少和骨组织形成降低。这些都说明了血管生成与骨质疏松症存在这密切联系。Kusumbe等[19]在骨骼系统中发现了一种新的具有不同形态、分子和功能特性的毛细管型，他们证实这些血管能够形成不同的代谢和分子微环境并调节骨脉管系统，维持血管-成骨细胞的耦联，而骨质疏松动物模型中该血管-成骨细胞的耦联急剧减少。

3 内皮祖细胞促进血管形成

内皮祖细胞(EPCs)是具有可分化为成熟内皮细胞能力的一种主要来源于骨髓和外周血的CD34+祖细胞亚群[20-21]，EPCs有益于血管的再生及保护，维持血管系统的稳定性[22]，近年有多组报道研究了EPCs在创伤愈合、骨折、心肌缺血、卒中、等动物模型中的治疗效应[21，23]。EPCs有早期EPCs和晚期EPCs之分，但这两类EPCs在新生血管形成启协同作用[24]，EPCs可在体外分化成内皮细胞而有助于脉管系统，且比成熟的内皮细胞具有更大的增殖容量[25]。Atesoket等[23]发现在骨折愈合阶段，EPC可促进新血管形成和骨再生。同样，Matsumoto等[26]的自体移植EPCs治疗发现EPCs的血管形成和骨再生的能力。EPCs对骨再生的具体机制并未明确，但可以肯定的是其血管形成能力对骨再生是必不可少的。

4 内皮祖细胞与成骨的关联

EPCs不仅具有分化成血管内皮细胞的功能，还可能具有分化为成骨细胞的能力。Lee等[27]证实了人脐血CD34+的内皮祖细胞刺激培养的人骨膜成骨细胞的成骨分化及形成矿化结节的能力；Duttenhoefer等[28]认为EPCs可分化前成骨细胞；Tondreau等[29]报道了一种EPC(外周血集落刺激因子CD133+细胞)可作为间充质干细胞促进骨生成；Pirro等[30]对绝经后女性调查研究发现，体内表达骨钙素或碱性磷酸酶的CD34+细胞数量增加可促进骨再生；Flammer等[31]对糖尿病患者调查发现，高糖化血红蛋白的这类患者体内可检测到高表达骨钙素蛋白的EPC。这些研究发生充分证明EPCs不仅可以促进血管生成，而且对骨再生有促进作用，EPCs能表达成骨相关蛋白，具有分化成成骨细胞的潜能从而使得成骨系细胞数目不断增多，最终抵制GC的骨形成抑制作用。

5 展望

在文章中所叙述相关动物实验和体内研究得出EPC能明显促进新生血管生成和促进骨再生。既然EPCs具有分化为成骨细胞的潜能和加强新生血管生成，改善局部血供和微环境，那么EPCs在骨质疏松性骨折，甚至预防和治疗与成骨功能低下及毛细血管数量减少所引起的骨质疏松症方面是否真正有效，现阶段研究的尚少，这需要在分子生物学机制的层面上进一步理解和探索。相信通过不断的研究与创新，体外扩增的自体EPC移植治疗将会成为包括骨质疏松、糖尿病等的受组织修复能力恢复的一个重要治疗方向。

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Research progress of correlation between osteoporosis and endothelial progenitor cells.

LIU Zhi-jun,KONG Jun-chao,ZENG Rong.Department of Orthopedics,the Affiliated Hospital of Guangdong Medical University,Zhanjiang 524000,Guangdong,CHINA

Endothelial progenitor cells are the subpopulation of cells that has potential of multi-directional differentiation,which can differentiate into osteoblasts and endothelial cells,and participate in angiogenesis and bone regeneration.Its applications in disease researches are also quite extensive.Bone cells apoptosis is the biological basis of glucocorticoid induced osteoporosis,and the concept of bone-vascular coupling suggests close correlation between osteogensis and angiogenesis.Based on the importance of vascular and osteoblast cells for osteoporosis,and the ability of endothelial cell differentiation and repair of tissue,this paper reviews the relationship between osteoporosis and endothelial progenitor cells.

Osteoporosis;Endothelial progenitor cells;Angiogenesis;Osteoblasts

R681

A

1003—6350（2017）07—1124—03

10.3969/j.issn.1003-6350.2017.07.032

2016-10-08)

国家自然科学基金（编号：81570260）

曾荣。E-mail：13802825311@139.com