骨質疏松癥與內皮祖細胞相關性研究進展

劉志軍，孔俊超，曾榮

(廣東醫科大學附屬醫院骨科，廣東湛江524000)

骨質疏松癥與內皮祖細胞相關性研究進展

劉志軍，孔俊超，曾榮

(廣東醫科大學附屬醫院骨科，廣東湛江524000)

內皮祖細胞是具有多方向分化的潛能的細胞亞群，可分化為血管內皮細胞和成骨細胞，參與血管形成及骨的再生，其在疾病研究的運用也相當廣泛。成骨系細胞凋亡是糖皮質激素性骨質疏松發生的生物學基礎，而骨-血管耦聯概念的提出，提示骨組織的血管發生與骨發生存在密切的交叉對話。基于血管與成骨系細胞方面對骨質疏松的重要性，以及內皮細胞的分化能力和對組織的修復能力，該文對骨質疏松癥與內皮祖細胞相關性作一綜述。

骨質疏松癥；內皮祖細胞；血管形成；成骨細胞

眾所周知，骨質疏松是一種以骨量減少、骨微細結構破壞并多數伴有骨痛為特征的全身性代謝性骨病，按病因可分為原發性和繼發性兩類[1]。骨質疏松癥患者骨組織內的成骨系細胞數目大量減少，骨骼脆性增加，在體質量或輕微損傷作用下，腰椎、股骨頸等負重骨易發生骨折[2]。原發性骨質疏松與衰老有關，隨年齡增長而出現；繼發性骨質疏松主要是由于藥物治療或一些疾病引起的并發癥，糖皮質激素性骨質疏松(GIOP)是其中最常見的一種[3]。隨著地塞米松(Dexamethasone，Dex)等外源性糖皮質激素(GC)在臨床上應用需求的增加，GIOP的發病率呈現不斷上升趨勢[2]。

1 骨質疏松與成骨系細胞間的聯系

目前臨床上防治GIOP的主要策略是在確保患者攝取足量鈣劑與維生素D的條件下，為其施用雙膦酸鹽類藥物[4]。該方法借鑒了治療原發性骨質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胞表面并引起其凋亡的特點，抑制破骨細胞骨吸收功能，能一定程度上緩解機體骨量減少的癥狀，但卻無法徹底阻斷GIOP病程進展[5]。這種現象產生的一個主要原因在于GIOP和原發性骨質疏松截然不同的發病機制：原發性骨質疏松是由于骨內膜表面下破骨細胞功能增加所致，其特征是皮質骨變薄，骨代謝處于骨吸收大于骨形成的失衡狀態[6]；而GIOP卻主要是由于GC對成骨細胞活性的抑制作用所引發的，表現為松質骨的骨形成減少。以破骨細胞為作用靶點的雙膦酸鹽類藥物由于不能增強成骨細胞活性，所以其阻斷GIOP發展的作用并不顯著[7]。由此亦可見，消除GC的骨形成抑制作用才是從根本上阻止GIOP進展的關鍵所在。骨重塑的過程中，破骨細胞的骨吸收與成骨細胞的骨形成間需要精準的平衡以保持骨的完整性[8]，在絕經后婦女中常發現的骨質疏松癥則是骨吸收與骨形成兩個過程不平衡導致[9]。病理學研究發現，GIOP骨組織內的BMMSCs、成骨細胞和骨細胞數明顯減少，且下降程度與GC應用劑量呈正比，而與此同時，破骨細胞的數量卻未出現顯著變化，提示GC的骨形成抑制作用與成骨系細胞數目減少有直接聯系[10]。

2 骨質疏松與血管的相關性

原發性或繼發性骨質疏松的發生發展也和骨血流灌注障礙有密切關系。滋養長骨的血管主要有滋養動脈、干骺端動脈、骺動脈、骨膜動脈這些動脈進入骨髓腔后形成皮質骨和骨髓微循環[11]。骨小梁和哈佛氏管表面的骨內膜、皮質骨內的哈佛氏管以及維持正常骨生長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皮細胞，內皮細胞不僅作為高滲透性的屏障也可分泌相關因子聚集如造血細胞促進骨生長[13-14]。研究發現，與骨骼生長有關的成骨細胞和血管生長間是有耦聯關系的，這表明內皮細胞和成骨細胞間具有分子交換[15]。Burkhardt等[16]觀察骨質疏松癥的骨組織學樣本發現與正常骨組織相比其單位面積內的竇狀毛細血管和動脈毛細血管數量是減少的；Qiang等[17]報道了骨血管化的減少與雌激素缺失介導的骨缺失的相關性；Tatsuno等[18]發現GIOP可引起骨髓血管減少和骨組織形成降低。這些都說明了血管生成與骨質疏松癥存在這密切聯系。Kusumbe等[19]在骨骼系統中發現了一種新的具有不同形態、分子和功能特性的毛細管型，他們證實這些血管能夠形成不同的代謝和分子微環境并調節骨脈管系統，維持血管-成骨細胞的耦聯，而骨質疏松動物模型中該血管-成骨細胞的耦聯急劇減少。

3 內皮祖細胞促進血管形成

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

4 內皮祖細胞與成骨的關聯

EPCs不僅具有分化成血管內皮細胞的功能，還可能具有分化為成骨細胞的能力。Lee等[27]證實了人臍血CD34+的內皮祖細胞刺激培養的人骨膜成骨細胞的成骨分化及形成礦化結節的能力；Duttenhoefer等[28]認為EPCs可分化前成骨細胞；Tondreau等[29]報道了一種EPC(外周血集落刺激因子CD133+細胞)可作為間充質干細胞促進骨生成；Pirro等[30]對絕經后女性調查研究發現，體內表達骨鈣素或堿性磷酸酶的CD34+細胞數量增加可促進骨再生；Flammer等[31]對糖尿病患者調查發現，高糖化血紅蛋白的這類患者體內可檢測到高表達骨鈣素蛋白的EPC。這些研究發生充分證明EPCs不僅可以促進血管生成，而且對骨再生有促進作用，EPCs能表達成骨相關蛋白，具有分化成成骨細胞的潛能從而使得成骨系細胞數目不斷增多，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動物實驗和體內研究得出EPC能明顯促進新生血管生成和促進骨再生。既然EPCs具有分化為成骨細胞的潛能和加強新生血管生成，改善局部血供和微環境，那么EPCs在骨質疏松性骨折，甚至預防和治療與成骨功能低下及毛細血管數量減少所引起的骨質疏松癥方面是否真正有效，現階段研究的尚少，這需要在分子生物學機制的層面上進一步理解和探索。相信通過不斷的研究與創新，體外擴增的自體EPC移植治療將會成為包括骨質疏松、糖尿病等的受組織修復能力恢復的一個重要治療方向。

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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)

國家自然科學基金（編號：81570260）

曾榮。E-mail：13802825311@139.com