梁冬科, 白小涓

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骨質(zhì)疏松和動(dòng)脈硬化共同機(jī)制的研究進(jìn)展

梁冬科1, 白小涓2*

（1中國(guó)醫(yī)科大學(xué)附屬第一醫(yī)院老年病科, 沈陽(yáng) 110001;2中國(guó)醫(yī)科大學(xué)附屬盛京醫(yī)院老年病干診科, 沈陽(yáng) 110004）

骨質(zhì)疏松和動(dòng)脈硬化都屬于受多因素影響，伴隨著衰老的退行性疾病。越來(lái)越多的研究證明二者之間存在聯(lián)系。近年來(lái)，有許多關(guān)于骨質(zhì)疏松和動(dòng)脈硬化共同發(fā)病機(jī)制的研究，并提出骨-血管軸的概念，即骨質(zhì)疏松和血管鈣化。熱點(diǎn)機(jī)制研究主要包括RANK/RANKL/OPG系統(tǒng)、氧化的脂質(zhì)、成纖維細(xì)胞生長(zhǎng)因子23/Klotho軸、胎球蛋白A和循環(huán)的鈣化細(xì)胞，本文對(duì)其進(jìn)行綜述。

骨密度; 骨質(zhì)疏松; 動(dòng)脈硬化

骨質(zhì)疏松和動(dòng)脈硬化都屬于受多因素影響，伴隨著衰老的退行性疾病。一些橫向和縱向的人群研究都證明二者之間存在聯(lián)系[1,2]。另外，骨密度低下者，發(fā)生心血管事件的風(fēng)險(xiǎn)增加[3]。反之，患有心血管病者，發(fā)生骨折的風(fēng)險(xiǎn)亦增加[4]。近年來(lái)，有許多關(guān)于骨質(zhì)疏松和動(dòng)脈硬化共同發(fā)病機(jī)制的研究，并提出骨-血管軸的概念[5,6]，即骨質(zhì)疏松和血管鈣化。熱點(diǎn)機(jī)制研究主要包括RANK/RANKL/OPG系統(tǒng)、氧化的脂質(zhì)、成纖維細(xì)胞生長(zhǎng)因子23/Klotho軸、胎球蛋白A和循環(huán)的鈣化細(xì)胞，本文對(duì)其進(jìn)行綜述。

1 RANK/RANKL/OPG系統(tǒng)

核因子кB受體活化因子（receptor activator of nuclear factor NF-κB，RANK）屬于腫瘤壞死因子受體家族成員，在破骨細(xì)胞前體和破骨細(xì)胞表面上表達(dá)。核因子κB受體活化因子配體（receptor activator of nuclear factor NF-κB ligand，RANKL）屬于腫瘤壞死因子家族成員，成骨細(xì)胞、T淋巴細(xì)胞、B淋巴細(xì)胞和巨核細(xì)胞都可以生成RANKL。RANK與RANKL結(jié)合后被激活，通過(guò)細(xì)胞內(nèi)信號(hào)傳導(dǎo)系統(tǒng)促進(jìn)破骨細(xì)胞的分化和成熟，激活破骨細(xì)胞，促進(jìn)骨吸收。骨保護(hù)素（osteoprotegerin，OPG）是一種可溶性糖蛋白，成骨細(xì)胞、骨髓基質(zhì)細(xì)胞可以分泌OPG。OPG與RANKL具有高度親和性，因此可以阻止RANKL與RANK結(jié)合，從而抑制破骨細(xì)胞的分化和活性，抑制骨吸收。RANK/RANKL/OPG系統(tǒng)在調(diào)節(jié)破骨細(xì)胞分化成熟以及活性方面發(fā)揮了重要作用。

RANK/RANKL/OPG系統(tǒng)在血管內(nèi)皮細(xì)胞、血管平滑肌細(xì)胞同樣有表達(dá)，在血管鈣化過(guò)程中發(fā)揮重要作用[7]。RANKL通過(guò)誘導(dǎo)人主動(dòng)脈內(nèi)皮細(xì)胞生成骨形成蛋白2和減少人主動(dòng)脈平滑肌細(xì)胞內(nèi)的基質(zhì)γ-羧基谷氨酸蛋白使血管發(fā)生鈣化[8]。OPG與血管鈣化、動(dòng)脈粥樣硬化、心血管病的關(guān)系目前尚存在爭(zhēng)議。體外實(shí)驗(yàn)發(fā)現(xiàn)OPG可以通過(guò)增加胰島素樣生長(zhǎng)因子1受體的表達(dá)和活性，抑制血管鈣化[9]。然而，臨床研究卻提示血清OPG水平升高與血管鈣化、冠心病有關(guān)，可以作為心血管病危險(xiǎn)因素之一，以及人群中心血管病和死亡率的預(yù)測(cè)指標(biāo)[10]，另外，近期研究發(fā)現(xiàn)高血壓患者血漿OPG水平高于血壓正常者，OPG可以作為監(jiān)測(cè)血管內(nèi)皮功能和預(yù)測(cè)心血管病的生物學(xué)標(biāo)志物[11]。以上研究結(jié)果提示OPG水平升高可能是一種機(jī)體自我保護(hù)機(jī)制。

2 氧化的脂質(zhì)

脂質(zhì)在血管內(nèi)皮沉積引起動(dòng)脈粥樣硬化，引起早發(fā)性和進(jìn)展迅速的心腦血管和周?chē)懿∽?。某些家族性血脂異常可于青春期前發(fā)生冠心病，甚至心肌梗死。近年研究發(fā)現(xiàn)，氧化的脂質(zhì)可導(dǎo)致骨代謝異常，引起骨質(zhì)疏松癥，其可能機(jī)制如下：（1）氧化的脂質(zhì)可以激活并誘導(dǎo)T淋巴細(xì)胞產(chǎn)生RANKL[12]，促進(jìn)破骨細(xì)胞的分化和成熟，激活破骨細(xì)胞，促進(jìn)骨吸收。（2）氧化的脂質(zhì)可以減弱成骨細(xì)胞的分化和增殖，并刺激成骨細(xì)胞凋亡，使骨形成減少[13]。（3）氧化的脂質(zhì)作用于成骨細(xì)胞，抑制無(wú)機(jī)磷酸鹽信號(hào)和無(wú)機(jī)磷酸鹽誘導(dǎo)的礦化作用[14]。

3 成纖維細(xì)胞生長(zhǎng)因子23/Klotho軸

成纖維細(xì)胞生長(zhǎng)因子23（fibroblast growth factor-23，F(xiàn)GF-23）是一種參與血磷調(diào)節(jié)的激素，由骨組織產(chǎn)生，作用于腎臟，控制磷的排泄和維生素D的生物合成。Klotho蛋白是一種膜蛋白，參與FGF-23的信號(hào)傳導(dǎo)，Klotho基因缺乏可使FGF-23與其受體的親和力下降，導(dǎo)致FGF-23無(wú)法調(diào)節(jié)磷的代謝[15]。FGF-23/Klotho軸通過(guò)以上機(jī)制間接影響骨代謝。近期的體外實(shí)驗(yàn)研究提示FGF-23/Klotho軸也可以直接作用于骨組織，抑制骨組織礦化[16]。

人群研究發(fā)現(xiàn)FGF-23水平與動(dòng)脈僵硬度和血管內(nèi)皮功能紊亂[17]以及嚴(yán)重的全身動(dòng)脈硬化[18]顯著相關(guān)。在慢性腎臟疾病和心血管病患者中，F(xiàn)GF-23水平獨(dú)立于心血管危險(xiǎn)因素和鈣磷水平，與全因死亡率和心血管事件的風(fēng)險(xiǎn)增加有關(guān)[19,20]。但是，在非慢性腎臟疾病和非心血管病患者中，F(xiàn)GF-23水平和心血管病病死率無(wú)關(guān)[21]。然而，動(dòng)物實(shí)驗(yàn)結(jié)果提示FGF-23水平升高與動(dòng)脈硬化的起始和進(jìn)展不直接相關(guān)，而磷水平升高可能起著重要作用，因?yàn)榱姿缴呖偸桥c血管鈣化有關(guān)，不論FGF-23水平如何[5]。FGF-23水平升高可能是為了保護(hù)骨組織、腎臟和血管，減少高磷血癥對(duì)它們的不利影響[22]。高磷血癥相關(guān)的血管細(xì)胞分化和鈣化的機(jī)制可能是通過(guò)磷酸鈣晶體誘導(dǎo)骨形成蛋白和骨橋蛋白的合成[23]。

4 胎球蛋白A

胎球蛋白A是體內(nèi)最強(qiáng)大的抑制礦化的蛋白質(zhì)，主要在肝臟合成，在血液循環(huán)中與鈣、磷等礦物質(zhì)前體結(jié)合形成復(fù)合體，即鈣-胎球蛋白顆粒，維持礦物離子的穩(wěn)定，不在肌肉、血管等其他軟組織沉積，最終在骨、牙齒的膠原纖維特定位置沉積[24]。無(wú)論哪種動(dòng)脈粥樣硬化斑塊鈣化的機(jī)制，如礦物質(zhì)內(nèi)環(huán)境紊亂、血脂異常、炎癥、細(xì)胞凋亡、基質(zhì)礦化或者骨生成，胎球蛋白A似乎能抵制許多上述機(jī)制，是礦化作用的系統(tǒng)調(diào)節(jié)者[25]。因此，胎球蛋白A的異?？赡苁枪琴|(zhì)疏松和動(dòng)脈硬化的共同發(fā)病機(jī)制的一種。動(dòng)物實(shí)驗(yàn)表明胎球蛋白A可以防止血管鈣化[26]。另一項(xiàng)針對(duì)心血管疾病患者的研究表明循環(huán)胎球蛋白A水平升高與高脂血癥和代謝綜合征的特征有關(guān)[27]。一些臨床研究發(fā)現(xiàn)心血管疾病風(fēng)險(xiǎn)增加與循環(huán)胎球蛋白A水平升高有關(guān)[28]，以上研究結(jié)果提示循環(huán)胎球蛋白A水平的升高可能是一種機(jī)體自我保護(hù)機(jī)制。

5 循環(huán)鈣化細(xì)胞

骨髓的間充質(zhì)和造血單位可以產(chǎn)生骨原細(xì)胞，骨重建的關(guān)鍵細(xì)胞成骨細(xì)胞和破骨細(xì)胞就分別起源于骨髓間充質(zhì)干細(xì)胞和造血干細(xì)胞，這些骨原細(xì)胞進(jìn)入血液循環(huán)后構(gòu)成循環(huán)鈣化細(xì)胞，主要包括以下類型：（1）間充質(zhì)骨祖細(xì)胞，起源于間充質(zhì)干細(xì)胞，抗原表型有CD44+、CD105+、CD73+、CD90+、CD34-、CD45-和CD14-；（2）CD34+造血祖細(xì)胞，起源于造血干細(xì)胞，抗原表型有CD34+、CD45+、骨鈣素（osteocalcin，OC）+和堿性磷酸酶（alkaline phosphatase，AP）+；（3）內(nèi)皮祖細(xì)胞，起源于造血干細(xì)胞，抗原表型有CD34+、血管內(nèi)皮生長(zhǎng)因子受體+、OC+和AP+；（4）骨髓鈣化細(xì)胞，起源于造血單位，抗原表型有CD14+、CD68+、CD45+、CD34-、CD44-、CD90-、CD29-、OC+和AP+。通過(guò)血液運(yùn)輸，這些具有成骨潛能的細(xì)胞成為骨重建和血管鈣化的主要調(diào)節(jié)者[6]。

臨床研究探索了不同循環(huán)鈣化細(xì)胞的作用，發(fā)現(xiàn)骨抗原（例如AP和OC）在CD34+細(xì)胞上的表達(dá)增加與骨質(zhì)疏松[29]和血管僵硬度增加[30]有關(guān)，Pirro 等發(fā)現(xiàn)骨質(zhì)疏松患者中AP+細(xì)胞減少，AP+/CD34+、OC+和OC+/CD34+細(xì)胞增加，說(shuō)明AP+細(xì)胞的減少與骨密度下降是密切相關(guān)的，AP+/CD34+細(xì)胞可能代表由骨髓動(dòng)員的有助于骨形成的未成熟細(xì)胞[29]。Pirro等還發(fā)現(xiàn)OC+/CD34+細(xì)胞增加與脈搏波速度加快有關(guān)[30]。骨質(zhì)疏松和血管鈣化通常與衰老有關(guān)，并且可以在一定情況下加速二者的發(fā)展，如慢性腎臟疾病、糖尿病和慢性阻塞性肺疾病[31-33]。而炎癥反應(yīng)在這些疾病的發(fā)生發(fā)展過(guò)程中起到了非常重要的作用，可以同時(shí)導(dǎo)致骨質(zhì)疏松和血管鈣化[31,34,35]。因此，可以推斷炎癥反應(yīng)是連接骨質(zhì)疏松、循環(huán)鈣化細(xì)胞和血管鈣化改變的關(guān)鍵點(diǎn)。

6 展 望

目前在治療學(xué)上已經(jīng)發(fā)現(xiàn)了二者之間的聯(lián)系。例如，他汀類調(diào)脂藥[36]和雙磷酸鹽類藥物[37]對(duì)骨質(zhì)疏松和動(dòng)脈硬化都有影響。另外，Kuroda等報(bào)道了使用CD34+細(xì)胞/內(nèi)皮祖細(xì)胞治療骨折成功的案例[38]。因此，骨質(zhì)疏松和動(dòng)脈硬化存在共同的發(fā)病機(jī)制，對(duì)其進(jìn)行進(jìn)一步研究，可以為骨質(zhì)疏松和動(dòng)脈硬化性疾病的防治尋找新的靶點(diǎn)。

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（編輯: 周宇紅）

Common mechanism of osteoporosis and arteriosclerosis: a review of recent advances

LIANG Dong-Ke1, BAI Xiao-Juan2*

(1Department of Gerontology and Geriatrics, First Affiliated Hospital, China Medical University, Shenyang 110001, China;2Department of Gerontology and Geriatrics, Shengjing Hospital, China Medical University, Shenyang 110004, China)

Osteoporosis and arteriosclerosis are both multifactorial, degenerative diseases that accompany aging. Many studies have suggested associations between osteoporosis and arteriosclerosis. In recent years, there are many studies investigating the common pathogenetic pathways of osteoporosis and arteriosclerosis. The meaning of bone-vascular axis is the associations between osteoporosis and vascular calcification. The hot research topics include RANK/RANKL/OPG system, oxidized lipids, fibroblast growth factor-23/Klotho axis, fetuin-A, and circulating calcifying cells. In this paper, we summarized the above pathogentic pathways.

bone mineral density; osteoporosis; arteriosclerosis

(2007CB507405, 2013CB530804),(No.2007225004).

R592; R59; R543.5

A

10.3724/SP.J.1264.2013.00088

2013-04-03;

2013-04-25

國(guó)家重點(diǎn)基礎(chǔ)研究發(fā)展計(jì)劃基金（2007CB507405; 2013CB530804）; 遼寧省科學(xué)技術(shù)廳課題基金（No.2007225004）

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