骨質(zhì)疏松癥與內(nèi)皮祖細(xì)胞相關(guān)性研究進(jìn)展

劉志軍，孔俊超，曾榮

(廣東醫(yī)科大學(xué)附屬醫(yī)院骨科，廣東湛江524000)

骨質(zhì)疏松癥與內(nèi)皮祖細(xì)胞相關(guān)性研究進(jìn)展

劉志軍，孔俊超，曾榮

(廣東醫(yī)科大學(xué)附屬醫(yī)院骨科，廣東湛江524000)

內(nèi)皮祖細(xì)胞是具有多方向分化的潛能的細(xì)胞亞群，可分化為血管內(nèi)皮細(xì)胞和成骨細(xì)胞，參與血管形成及骨的再生，其在疾病研究的運(yùn)用也相當(dāng)廣泛。成骨系細(xì)胞凋亡是糖皮質(zhì)激素性骨質(zhì)疏松發(fā)生的生物學(xué)基礎(chǔ)，而骨-血管耦聯(lián)概念的提出，提示骨組織的血管發(fā)生與骨發(fā)生存在密切的交叉對(duì)話(huà)。基于血管與成骨系細(xì)胞方面對(duì)骨質(zhì)疏松的重要性，以及內(nèi)皮細(xì)胞的分化能力和對(duì)組織的修復(fù)能力，該文對(duì)骨質(zhì)疏松癥與內(nèi)皮祖細(xì)胞相關(guān)性作一綜述。

骨質(zhì)疏松癥；內(nèi)皮祖細(xì)胞；血管形成；成骨細(xì)胞

眾所周知，骨質(zhì)疏松是一種以骨量減少、骨微細(xì)結(jié)構(gòu)破壞并多數(shù)伴有骨痛為特征的全身性代謝性骨病，按病因可分為原發(fā)性和繼發(fā)性?xún)深?lèi)[1]。骨質(zhì)疏松癥患者骨組織內(nèi)的成骨系細(xì)胞數(shù)目大量減少，骨骼脆性增加，在體質(zhì)量或輕微損傷作用下，腰椎、股骨頸等負(fù)重骨易發(fā)生骨折[2]。原發(fā)性骨質(zhì)疏松與衰老有關(guān)，隨年齡增長(zhǎng)而出現(xiàn)；繼發(fā)性骨質(zhì)疏松主要是由于藥物治療或一些疾病引起的并發(fā)癥，糖皮質(zhì)激素性骨質(zhì)疏松(GIOP)是其中最常見(jiàn)的一種[3]。隨著地塞米松(Dexamethasone，Dex)等外源性糖皮質(zhì)激素(GC)在臨床上應(yīng)用需求的增加，GIOP的發(fā)病率呈現(xiàn)不斷上升趨勢(shì)[2]。

1 骨質(zhì)疏松與成骨系細(xì)胞間的聯(lián)系

目前臨床上防治GIOP的主要策略是在確?；颊邤z取足量鈣劑與維生素D的條件下，為其施用雙膦酸鹽類(lèi)藥物[4]。該方法借鑒了治療原發(fā)性骨質(zhì)疏松的臨床用藥原則，利用雙膦酸鹽可特異性聚集在破骨細(xì)胞表面并引起其凋亡的特點(diǎn)，抑制破骨細(xì)胞骨吸收功能，能一定程度上緩解機(jī)體骨量減少的癥狀，但卻無(wú)法徹底阻斷GIOP病程進(jìn)展[5]。這種現(xiàn)象產(chǎn)生的一個(gè)主要原因在于GIOP和原發(fā)性骨質(zhì)疏松截然不同的發(fā)病機(jī)制：原發(fā)性骨質(zhì)疏松是由于骨內(nèi)膜表面下破骨細(xì)胞功能增加所致，其特征是皮質(zhì)骨變薄，骨代謝處于骨吸收大于骨形成的失衡狀態(tài)[6]；而GIOP卻主要是由于GC對(duì)成骨細(xì)胞活性的抑制作用所引發(fā)的，表現(xiàn)為松質(zhì)骨的骨形成減少。以破骨細(xì)胞為作用靶點(diǎn)的雙膦酸鹽類(lèi)藥物由于不能增強(qiáng)成骨細(xì)胞活性，所以其阻斷GIOP發(fā)展的作用并不顯著[7]。由此亦可見(jiàn)，消除GC的骨形成抑制作用才是從根本上阻止GIOP進(jìn)展的關(guān)鍵所在。骨重塑的過(guò)程中，破骨細(xì)胞的骨吸收與成骨細(xì)胞的骨形成間需要精準(zhǔn)的平衡以保持骨的完整性[8]，在絕經(jīng)后婦女中常發(fā)現(xiàn)的骨質(zhì)疏松癥則是骨吸收與骨形成兩個(gè)過(guò)程不平衡導(dǎo)致[9]。病理學(xué)研究發(fā)現(xiàn)，GIOP骨組織內(nèi)的BMMSCs、成骨細(xì)胞和骨細(xì)胞數(shù)明顯減少，且下降程度與GC應(yīng)用劑量呈正比，而與此同時(shí)，破骨細(xì)胞的數(shù)量卻未出現(xiàn)顯著變化，提示GC的骨形成抑制作用與成骨系細(xì)胞數(shù)目減少有直接聯(lián)系[10]。

2 骨質(zhì)疏松與血管的相關(guān)性

原發(fā)性或繼發(fā)性骨質(zhì)疏松的發(fā)生發(fā)展也和骨血流灌注障礙有密切關(guān)系。滋養(yǎng)長(zhǎng)骨的血管主要有滋養(yǎng)動(dòng)脈、干骺端動(dòng)脈、骺動(dòng)脈、骨膜動(dòng)脈這些動(dòng)脈進(jìn)入骨髓腔后形成皮質(zhì)骨和骨髓微循環(huán)[11]。骨小梁和哈佛氏管表面的骨內(nèi)膜、皮質(zhì)骨內(nèi)的哈佛氏管以及維持正常骨生長(zhǎng)都必須有血管生成的參與[12]，而血管的最重要組成部分之一是內(nèi)皮細(xì)胞，內(nèi)皮細(xì)胞不僅作為高滲透性的屏障也可分泌相關(guān)因子聚集如造血細(xì)胞促進(jìn)骨生長(zhǎng)[13-14]。研究發(fā)現(xiàn)，與骨骼生長(zhǎng)有關(guān)的成骨細(xì)胞和血管生長(zhǎng)間是有耦聯(lián)關(guān)系的，這表明內(nèi)皮細(xì)胞和成骨細(xì)胞間具有分子交換[15]。Burkhardt等[16]觀察骨質(zhì)疏松癥的骨組織學(xué)樣本發(fā)現(xiàn)與正常骨組織相比其單位面積內(nèi)的竇狀毛細(xì)血管和動(dòng)脈毛細(xì)血管數(shù)量是減少的；Qiang等[17]報(bào)道了骨血管化的減少與雌激素缺失介導(dǎo)的骨缺失的相關(guān)性；Tatsuno等[18]發(fā)現(xiàn)GIOP可引起骨髓血管減少和骨組織形成降低。這些都說(shuō)明了血管生成與骨質(zhì)疏松癥存在這密切聯(lián)系。Kusumbe等[19]在骨骼系統(tǒng)中發(fā)現(xiàn)了一種新的具有不同形態(tài)、分子和功能特性的毛細(xì)管型，他們證實(shí)這些血管能夠形成不同的代謝和分子微環(huán)境并調(diào)節(jié)骨脈管系統(tǒng)，維持血管-成骨細(xì)胞的耦聯(lián)，而骨質(zhì)疏松動(dòng)物模型中該血管-成骨細(xì)胞的耦聯(lián)急劇減少。

3 內(nèi)皮祖細(xì)胞促進(jìn)血管形成

內(nèi)皮祖細(xì)胞(EPCs)是具有可分化為成熟內(nèi)皮細(xì)胞能力的一種主要來(lái)源于骨髓和外周血的CD34+祖細(xì)胞亞群[20-21]，EPCs有益于血管的再生及保護(hù)，維持血管系統(tǒng)的穩(wěn)定性[22]，近年有多組報(bào)道研究了EPCs在創(chuàng)傷愈合、骨折、心肌缺血、卒中、等動(dòng)物模型中的治療效應(yīng)[21，23]。EPCs有早期EPCs和晚期EPCs之分，但這兩類(lèi)EPCs在新生血管形成啟協(xié)同作用[24]，EPCs可在體外分化成內(nèi)皮細(xì)胞而有助于脈管系統(tǒng)，且比成熟的內(nèi)皮細(xì)胞具有更大的增殖容量[25]。Atesoket等[23]發(fā)現(xiàn)在骨折愈合階段，EPC可促進(jìn)新血管形成和骨再生。同樣，Matsumoto等[26]的自體移植EPCs治療發(fā)現(xiàn)EPCs的血管形成和骨再生的能力。EPCs對(duì)骨再生的具體機(jī)制并未明確，但可以肯定的是其血管形成能力對(duì)骨再生是必不可少的。

4 內(nèi)皮祖細(xì)胞與成骨的關(guān)聯(lián)

EPCs不僅具有分化成血管內(nèi)皮細(xì)胞的功能，還可能具有分化為成骨細(xì)胞的能力。Lee等[27]證實(shí)了人臍血CD34+的內(nèi)皮祖細(xì)胞刺激培養(yǎng)的人骨膜成骨細(xì)胞的成骨分化及形成礦化結(jié)節(jié)的能力；Duttenhoefer等[28]認(rèn)為EPCs可分化前成骨細(xì)胞；Tondreau等[29]報(bào)道了一種EPC(外周血集落刺激因子CD133+細(xì)胞)可作為間充質(zhì)干細(xì)胞促進(jìn)骨生成；Pirro等[30]對(duì)絕經(jīng)后女性調(diào)查研究發(fā)現(xiàn)，體內(nèi)表達(dá)骨鈣素或堿性磷酸酶的CD34+細(xì)胞數(shù)量增加可促進(jìn)骨再生；Flammer等[31]對(duì)糖尿病患者調(diào)查發(fā)現(xiàn)，高糖化血紅蛋白的這類(lèi)患者體內(nèi)可檢測(cè)到高表達(dá)骨鈣素蛋白的EPC。這些研究發(fā)生充分證明EPCs不僅可以促進(jìn)血管生成，而且對(duì)骨再生有促進(jìn)作用，EPCs能表達(dá)成骨相關(guān)蛋白，具有分化成成骨細(xì)胞的潛能從而使得成骨系細(xì)胞數(shù)目不斷增多，最終抵制GC的骨形成抑制作用。

5 展望

在文章中所敘述相關(guān)動(dòng)物實(shí)驗(yàn)和體內(nèi)研究得出EPC能明顯促進(jìn)新生血管生成和促進(jìn)骨再生。既然EPCs具有分化為成骨細(xì)胞的潛能和加強(qiáng)新生血管生成，改善局部血供和微環(huán)境，那么EPCs在骨質(zhì)疏松性骨折，甚至預(yù)防和治療與成骨功能低下及毛細(xì)血管數(shù)量減少所引起的骨質(zhì)疏松癥方面是否真正有效，現(xiàn)階段研究的尚少，這需要在分子生物學(xué)機(jī)制的層面上進(jìn)一步理解和探索。相信通過(guò)不斷的研究與創(chuàng)新，體外擴(kuò)增的自體EPC移植治療將會(huì)成為包括骨質(zhì)疏松、糖尿病等的受組織修復(fù)能力恢復(fù)的一個(gè)重要治療方向。

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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)

國(guó)家自然科學(xué)基金（編號(hào)：81570260）

曾榮。E-mail：13802825311@139.com