朱音 舒冰 王擁軍 王晶
摘要 骨質(zhì)疏松癥(Osteoporosis,OP)是一種以骨量低下、骨微結(jié)構(gòu)破壞,導(dǎo)致脆性骨折的退行性骨病。阿爾茨海默病(Alzheimer′s Disease,AD)主要表現(xiàn)為記憶力減退和認(rèn)知功能障礙。表面上看OP和AD不論是在癥狀還是在體征方面都截然不同,但越來越多的研究表明兩者存在一些共有的致病因素、發(fā)病機(jī)制和信號通路。
關(guān)鍵詞 骨質(zhì)疏松;阿爾茨海默??;骨密度;淀粉樣蛋白
Abstract Osteoporosis (OP) can be defined as a degenerative bone disease characterized by low bone mass and the microarchitectural deterioration, with a consequent increase in the fragility of bone and susceptibility to fracture. Alzheimer′s disease (AD) is a disease with memory loss and cognitive impairment. Despite their different signs and symptoms, these two diseases share many common risk factors, pathogenesis and signaling pathways.
Key Words Osteoporosis; Alzheimer disease; Bone density; Amyloid
中圖分類號:R714;R257文獻(xiàn)標(biāo)識碼:Adoi:10.3969/j.issn.1673-7202.2018.02.066
骨質(zhì)疏松癥(Osteoporosis,OP)是一種以骨量低下、骨微結(jié)構(gòu)破壞,導(dǎo)致脆性骨折的退行性骨病。阿爾茨海默?。ˋlzheimer′s Disease,AD)即老年性癡呆,主要表現(xiàn)為記憶力減退和認(rèn)知功能障礙。表面上看OP和AD不論是在癥狀還是在體征方面都截然不同,但越來越多的研究表明兩者存在一些共有的信號通路[1-3],且AD患者更易罹患OP[4-5],現(xiàn)就OP與AD的相關(guān)性做一簡要綜述。
1 分類綜述
1.1 流行病學(xué)
1.1.1 OP的流行病學(xué)調(diào)查研究
發(fā)達(dá)國家的OP發(fā)病率男性為2%~8%不等,女性為9%~38%不等[6]。絕經(jīng)后由于雌激素減少,女性的骨量流失速度明顯快于男性,同時女性的預(yù)期壽命普遍高于男性,男性骨質(zhì)疏松性骨折的死亡率又高于女性,這些原因都導(dǎo)致女性O(shè)P患者多于男性。而這樣的性別差異在OP的標(biāo)準(zhǔn)化死亡率方面也有跡可循。丹麥的一項(xiàng)隊(duì)列研究發(fā)現(xiàn)確診后接受治療的50歲男性O(shè)P患者剩余預(yù)期壽命為18.2年,75歲男性患者為7.5年,而這一數(shù)字在50歲和75歲女性O(shè)P患者中分別為26.4年和13.5年[7]。
在我國OP的發(fā)病特征不僅表現(xiàn)為女性多于男性(25.41%比15.33%),還表現(xiàn)為農(nóng)村多于城市(23.92%比20.87%)、南方多于北方(23.17%比20.13%),2012—2015年我國的OP發(fā)病率為27.96%,80歲及以上老年人的發(fā)病率則高達(dá)56.1%[8],可見OP與增齡密切相關(guān)。除此之外,缺乏體育鍛煉、低維生素D水平、吸煙、飲酒和高咖啡因也會降低骨密度(Bone Mineral Density,BMD)從而導(dǎo)致OP[9]。意大利的一項(xiàng)調(diào)查則證實(shí)體質(zhì)量、甲狀腺功能亢進(jìn)、腎結(jié)石、克羅恩病、潰瘍性結(jié)腸炎、乳糜瀉、缺乏日照和50歲前卵巢切除史都有可能是OP的預(yù)測因素[10]。當(dāng)然OP的發(fā)病也與骨保護(hù)素(Osteoprotegerin,OPG)、核因子-κB受體活化因子(Receptor Activator of NF-κB,RANK)、核因子-κB受體激活配體(Receptor Activator of Nuclear Factor kappa-B Ligand,RANKL)、低密度脂蛋白受體相關(guān)蛋白(Low Density Lipoprotein Receptor Related Protein,LRP)4/5、雌激素受體1、主要組織相容性復(fù)合體和骨硬化蛋白等基因相關(guān)[11],是環(huán)境、飲食及遺傳等多因素共同作用的結(jié)果。
1.1.2 AD的流行病學(xué)調(diào)查研究
薈萃分析發(fā)現(xiàn)我國的AD患者數(shù)量在1990年、2000年和2010年分別為193萬、371萬和569萬[12]。臺灣全民健康保險研究資料庫顯示,2005—2010年臺灣地區(qū)確診的AD患者女性多于男性(54%比46%),年齡多在75~84歲之間,發(fā)病率由2005年的5.63/千人年上升至2010年的8.17/千人年,且6年的累計(jì)發(fā)病率為33.54‰[13]。AD的發(fā)病率和患病率都隨著年齡的增長而呈指數(shù)級增長,尤其多見于65歲以上的老年人。以歐洲和美國為例,2002—2012年的AD發(fā)病率為3%~7%不等,其中英國(45~65歲)為0.04/千人年,美國(≥65歲)為16.8/千人年[14]。根據(jù)2010年的美國人口普查,470萬65歲及以上AD患者中將近60萬死亡,據(jù)保守估計(jì)到2050年AD的患者數(shù)和死亡數(shù)可達(dá)1380萬和160萬[15]。
前瞻性研究發(fā)現(xiàn)AD患者的BMD和血漿瘦素水平均低于非AD人群。低BMD、骨量丟失的速率、吸煙及日常飲酒都會增加AD的患病風(fēng)險,而高瘦素水平則能預(yù)防AD。進(jìn)一步研究發(fā)現(xiàn)OP、高血壓、糖尿病和高脂血癥能加快輕度認(rèn)知障礙的認(rèn)知功能下降,低BMD、高血壓、糖尿病、高脂血癥和低25-羥維生素D水平和高OPG均與AD的發(fā)病相關(guān)[16]。
1.2 發(fā)病機(jī)制
無論女性還是男性,在其峰值骨量維持期后進(jìn)入骨量丟失期,表現(xiàn)為相對或絕對的骨吸收大于骨形成。尤其是女性患者更年期卵巢功能中斷,加速了絕經(jīng)后骨量的丟失,出現(xiàn)過度的骨吸從而導(dǎo)致OP。而AD的典型病理特征是β-淀粉樣蛋白(Amyloid Beta,Aβ)為核心的老年斑、tau蛋白高度磷酸化形成的細(xì)胞內(nèi)神經(jīng)元纖維纏結(jié)(Neurofibrillary Tangles,NFTs)和神經(jīng)元細(xì)胞減少。基于OP與AD的共同致病因素,研究者們試圖從發(fā)病機(jī)制入手尋找兩者的相關(guān)性。
1.2.1 雌激素 Lee等[17]通過檢測不同程度認(rèn)知障礙的女性BMD發(fā)現(xiàn)認(rèn)知損害與低BMD有關(guān),簡易精神狀態(tài)檢查與BMD呈正相關(guān),臨床癡呆評定量表與BMD呈負(fù)相關(guān),提示雌激素缺乏可能是認(rèn)知功能減退的誘因之一?,F(xiàn)有研究認(rèn)為雌激素的神經(jīng)保護(hù)功能除了能調(diào)節(jié)突觸可塑性外還主要得益于:1)腦內(nèi)存在的雌激素受體;2)調(diào)節(jié)認(rèn)知過程的神經(jīng)傳導(dǎo)物質(zhì);3)防止Aβ沉積、氧化損傷、缺血性卒中和細(xì)胞凋亡。而雌激素缺乏也會引起絕經(jīng)后婦女骨量減少。雌性嚙齒類動物卵巢切除術(shù)后,低雌激素水平會增加骨量的流失,并出現(xiàn)骨質(zhì)疏松基因表型[18]。若給予持續(xù)依賴的雌激素治療能夠提高BMD,防止骨質(zhì)疏松性骨折[19]。目前已知雌激素主要通過增加成骨細(xì)胞(Osteoblast,OB)促進(jìn)骨形成,抑制高骨轉(zhuǎn)換從而防止骨量流失[20]。研究發(fā)現(xiàn)語言記憶障礙的發(fā)病隨著股骨頸BMD升高而降低,調(diào)整吸煙、飲酒等因素后,BMD和語言記憶障礙之間的相關(guān)性明顯減小,由此推斷BMD與語言記憶障礙之間的生物學(xué)機(jī)制是雌激素暴露[21]。
1.2.2 Wnt信號通路 研究顯示W(wǎng)nt信號通路與OP和AD都密切相關(guān)。Wnt在大腦內(nèi)參與軸突導(dǎo)向、神經(jīng)母細(xì)胞遷移和神經(jīng)元增殖、分化[22],同時也對OB分化起到重要作用[23]。Dickkopf相關(guān)蛋白1(Dickkopf-relative Protein1,Dkk1)作為該信號通路的重要拮抗劑,是大腦和骨骼的重要分子鏈[24],其活性受到LRP調(diào)控。Dkk1通過與Wnt競爭結(jié)合LRP6,阻斷Wnt/β-catenin,從而抑制骨形成。研究證實(shí)血清Dkk1水平與骨密度呈負(fù)相關(guān)[25],抑制Dkk1能促進(jìn)OB分化和骨形成[26],防止全身骨量流失,敲除Dkk1基因有助于增加骨量提高BMD[27]。Fujita等[28]發(fā)現(xiàn)Dkk1能抑制OB分化和成熟,并上調(diào)OPG和RANKL的表達(dá),可見Dkk1在平衡骨形成和骨吸收中起著重要作用。另一方面Dkk1的抑制作用與Aβ和tau蛋白過度磷酸化的神經(jīng)毒性都有關(guān)。在轉(zhuǎn)基因AD鼠腦內(nèi)發(fā)現(xiàn)Aβ沉積會引起Dkk1表達(dá)和分泌增加,間接導(dǎo)致突觸丟失和神經(jīng)元細(xì)胞凋亡[29]。激活Wnt信號通路卻能減少β-淀粉樣前體蛋白裂解酶1(Aβ Precursor Protein Cleaving Enzyme 1,BACE1)[30],而Dkk1過表達(dá)能通過抑制Wnt信號通路引起tau蛋白過度磷酸化[31]。上述研究都證實(shí)Dkk1在腦內(nèi)高表達(dá)可以增加AD的風(fēng)險,提示Dkk1可能是OP和AD共有的危險因素。
1.2.3 核轉(zhuǎn)錄因子-κB(Nuclear Transcription Factor Kappa B,NF-κB)信號通路 OB分泌OPG,破骨細(xì)胞(Osteoclast,OC)分泌RANK。RANK能與RANKL結(jié)合,激活OC分化。而OPG與RANK存在競爭性抑制,能與RANKL結(jié)合,進(jìn)而抑制OC分化與成熟。OPG基因敲除小鼠會出現(xiàn)早發(fā)型OP[32],RANKL突變小鼠則表現(xiàn)為骨硬化癥[33]。已知NF-κB信號通路在炎性反應(yīng)過程中發(fā)揮著重要作用,長期暴露于炎性反應(yīng)環(huán)境下可以明顯激活NF-κB,抑制OB的功能及骨髓間充質(zhì)干細(xì)胞向OB定向分化的能力[34]。而該信號通路的激活也與NFTs和細(xì)胞外Aβ沉積有關(guān)。AD腦內(nèi)炎性因子增高會促進(jìn)淀粉樣蛋白前體(Amyloid Precursor Protein,APP)降解生成Aβ,Aβ激活NF-κB介導(dǎo)炎性因子表達(dá),炎性因子再次作用于APP產(chǎn)生Aβ的惡性循環(huán),這種級聯(lián)反應(yīng)在AD的發(fā)病中至關(guān)重要[35]。這就意味著抑制NF-κB激活能明顯減輕Aβ所致的炎性反應(yīng),降低炎性因子對神經(jīng)元細(xì)胞的損害,同時減少NFTs和Aβ沉積。Li等[36]在大鼠骨髓單核細(xì)胞中發(fā)現(xiàn)Aβ對RANKL介導(dǎo)的OC生成并無作用,但能促進(jìn)骨吸收。在分子層面,Aβ可以增強(qiáng)NF-κB的活性,激活細(xì)胞外調(diào)節(jié)蛋白激酶(Extracellular Regulated Protein,ERK)磷酸化并刺激鈣離子震蕩,引起破骨細(xì)胞活化T細(xì)胞核因子表達(dá)上調(diào)。上述研究證明激活NF-κB會導(dǎo)致OP和AD。
1.2.4 淀粉樣蛋白前體 體內(nèi)APP裂解后產(chǎn)生Aβ,當(dāng)Aβ透過血腦屏障發(fā)生轉(zhuǎn)運(yùn)障礙時,Aβ寡聚體形成、沉積,產(chǎn)生神經(jīng)毒性,最終造成神經(jīng)功能障礙和細(xì)胞凋亡。此外,大量聚集的Aβ可以通過激活星形膠質(zhì)細(xì)胞或小膠質(zhì)細(xì)胞釋放炎性因子,觸發(fā)神經(jīng)損傷通路,引起神經(jīng)毒性。體內(nèi)外研究發(fā)現(xiàn)APP和Aβ能夠調(diào)節(jié)OC分化。Li等[37]活檢骨組織后發(fā)現(xiàn),與對照組比較,OP患者和去卵巢大鼠的Aβ42、APP在mRNA及蛋白表達(dá)方面都顯著增高,且與BMD呈負(fù)相關(guān)。APP主要位于骨細(xì)胞膜,而Aβ42除了出現(xiàn)在上述部位外,還沉積于細(xì)胞質(zhì)及細(xì)胞外基質(zhì)。Aβ42雖能有效增強(qiáng)OC的分化與激活,但并不影響后者的活性與數(shù)量。Tg2576鼠是基于調(diào)控朊病毒表達(dá)的一種瑞典APP基因突變小鼠,對OC的激活具有雙向調(diào)節(jié)作用。Cui等[38]在4月齡以下的Tg2576小鼠模型中發(fā)現(xiàn)Aβ寡聚體和晚期糖化終末產(chǎn)物受體(Receptor for Advanced Glycation End products,RAGE)會促進(jìn)OC生成。而在4月齡以上的Tg2576小鼠中RAGE增多卻減少了OC的形成和活性,主要是因?yàn)镽AGE是通過抑制RANKL誘導(dǎo)了OC生成。提示AD患者調(diào)節(jié)骨重建的潛在機(jī)制,提示APP/Aβ是AD與OP的共同特性。
1.3 用藥規(guī)律 臨床上主要以雙磷酸鹽類、降鈣素類、雌激素類來抑制骨吸收,同時中藥、體育運(yùn)動、戒煙、鈣劑和維生素D等支持療法也有助于改善OP。AD的治療方法多集中于防止Aβ生成或增加腦內(nèi)Aβ清除。治療藥物包括:膽堿酶抑制、興奮性氨基酸受體拮抗劑、抗氧化劑、腦代謝增強(qiáng)劑、中藥以及抗精神病藥物。目前尚無逆轉(zhuǎn)AD的藥物,只能改善癥狀和延緩病程。鑒于OP和AD在誘發(fā)因素和發(fā)病機(jī)制上的共性,研究者們開展了一系列對癥治療,中醫(yī)藥治療由于不良反應(yīng)少療效明顯。
目前臨床上約有33種中藥方劑用于治療OP,有效組分有黃酮類、木酚類、皂苷類及環(huán)烯醚萜苷類,作用機(jī)制包含Wnt/β-catenin、BMP/Smad、MAPK信號通路和RANKL/OPG系統(tǒng)[39]。在臺灣地區(qū),獨(dú)活寄生湯和杜仲是最長用的方劑和單味藥[40]。研究發(fā)現(xiàn)多數(shù)補(bǔ)腎中藥都能作用于骨代謝,例如淫羊藿、女貞子和補(bǔ)骨脂,將這3味中藥組成的方劑既能作用于成骨也能抗破骨,保護(hù)BMD[41]。Liu等[42]進(jìn)一步研究發(fā)現(xiàn)淫羊藿和女貞子的混合提取物能夠改善BMD,影響骨組織形態(tài),整合下丘腦-垂體-性腺軸的激素水平,提高性激素受體的蛋白及mRNA表達(dá)。
Aβ引起的線粒體功能障礙是AD的一個重要特點(diǎn)。作為淫羊藿的活性組分,淫羊藿苷能夠促進(jìn)線粒體轉(zhuǎn)運(yùn),增強(qiáng)細(xì)胞活性,減少Aβ25-35引起的細(xì)胞凋亡,降低海馬內(nèi)Aβ、老年斑、APP和BACE1水平,抑制Aβ生成及tau蛋白過度磷酸化,改善AD患者的空間學(xué)習(xí)能力和記憶力[43-45]。柴胡皂苷C則對Aβ及tau蛋白有著雙向作用,可以顯著抑制Aβ1-40、Aβ1-42釋放,加速神經(jīng)生長因子介導(dǎo)的神經(jīng)突生長及微管的集合,但并不影響B(tài)ACE1的活性和表達(dá)[46]。也有研究發(fā)現(xiàn)了芍藥苷的神經(jīng)保護(hù)作用,包括減少線粒體膜電位、促進(jìn)細(xì)胞色素C釋放、激活天冬氨酸特異性半胱氨酸蛋白酶3/9,從而減輕/恢復(fù)Aβ25-35對PC12細(xì)胞引起的損傷[47]。這些研究都給OP和AD的治療方法提供了嶄新的思路。
2 小結(jié)
目前對于OP與AD相關(guān)性的研究較少,又都集中于動物試驗(yàn),缺乏大樣本的臨床流行病學(xué)研究。已經(jīng)證實(shí),OP與AD的共同致病因素有高齡、女性、吸煙、酗酒、雌激素下降和維生素D水平[[48]]。共有的信號通路與相似的用藥規(guī)律也提示這2種疾病的相關(guān)性,然而OP與AD互為相關(guān)的作用途徑以及Aβ在激活OC中起到的作用仍是未知,還需通過試驗(yàn)和臨床研究進(jìn)一步加以闡述。
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