陳祥和 李文秀 劉 波 殷榮賓

骨源性因子ucOCN在運動抗抑郁中的作用機制*

陳祥和1李文秀1劉 波1殷榮賓2

(1揚州大學體育學院, 江蘇 揚州 225127) (2蘇州大學體育學院, 江蘇 蘇州 215000)

羧化不全骨鈣素(ucOCN)是骨中成骨細胞分泌的特異性蛋白, 因其在調控神經發(fā)育、神經可塑性等中的重要角色而受到神經科學領域關注?！肮?腦”串聯(lián)“對話”是骨內分泌?神經介導的應答系統(tǒng), ucOCN透過血腦屏障后介導單胺類神經遞質、神經內分泌、神經免疫、神經再生及基因表達等機制, 進而作用于海馬CA3區(qū)、扣帶回等腦區(qū)功能發(fā)揮來調節(jié)抑郁發(fā)生及改善。而ucOCN作為骨源性力學刺激敏感基因, 運動上調其表達后進入血液循環(huán), 通過介導5-HT/GABA分泌、HPA軸功能、炎癥反應、神經營養(yǎng)因子(BDNF等)表達或信號途徑(如GSK3β/β-catenin、TLR4/miR-223/NLRP3等)激活等來實現(xiàn)“骨串聯(lián)腦”, 發(fā)揮運動抗抑郁作用。通過對骨源性因子ucOCN介導腦區(qū)功能變化從而實現(xiàn)運動抗抑郁的作用機制進行探討、梳理, 一方面有助于更深入了解骨內分泌功能, 另一方面為抑郁發(fā)生、改善和運動抗抑郁研究提供新的理論基礎和研究思路。

羧化不全骨鈣素, 骨, 腦, 運動, 抑郁癥

抑郁癥不僅是社會重大焦點問題, 其發(fā)病機制探究亦是神經科學領域的研究熱點。研究發(fā)現(xiàn), 單胺類神經遞質分泌、下丘腦?垂體?腎上腺軸(Hypothalamic–pituitary–adrenal axis, HPA)、細胞因子表達等功能的失調, 可通過作用于眶皮質區(qū)、海馬扣帶回及下丘腦等腦內結構, 調控中縫核及其軸突路徑相關結構內神經元中神經遞質如5-羥色胺(5-hydroxytryptamine, 5-HT)）分泌、關鍵因子表達等, 進而影響抑郁的發(fā)生、發(fā)展?，F(xiàn)已證實的抑郁癥發(fā)病機制主要有：單胺類神經遞質假說、基因?環(huán)境相互作用、神經發(fā)生、神經可塑性、免疫激活與抑制等(Frye & Walf, 2009)。骨鈣素(Osteocalcin, OCN)作為骨中成骨細胞(Osteoblast, OB)分泌的特異性非膠原蛋白(Lin et al., 2020), 其活化形式羧化不全骨鈣素(Uncarboxylated osteocalcin, ucOCN)經生物信號刺激后, 由骨分泌入血后作用于胰島β細胞、睪丸、脂肪、腦等組織器官, 通過靶細胞膜受體引起級聯(lián)反應調控能量代謝、精子形成、認知功能障礙等(Vella & Kumar, 2013)。

OB具有內分泌功能, 將OB上的ucOCN基因敲除后, ucOCN-/-小鼠記憶力和空間學習能力下降且出現(xiàn)抑郁樣行為; 而注射外源性ucOCN后, ucOCN-/-小鼠抑郁樣行為顯著改善(Khrimian et al., 2017)。提示, OB分泌的特異性ucOCN在抑郁發(fā)生上具有“骨?腦Crosstalk”調控作用。運動是改善抑郁的有效手段, 但相關研究焦點集中于中樞神經系統(tǒng)可塑性適應變化上。近來發(fā)現(xiàn), OB中的ucOCN作為運動敏感基因, 其活化入血穿過血腦屏障后與G蛋白偶聯(lián)受體158 (G protein-coupled receptors 158, Gpr158)結合調節(jié)靶基因腦源性神經營養(yǎng)因子(Brain-derived neurotrophic factor, BDNF)表達, 調控抑郁發(fā)生、改善(Khrimian et al., 2017)。國內劉微娜團隊在探究運動抗抑郁時提出了：“腦?腸互動”、“肌?腦Crosstalk”、脂肪細胞因子等理論(薛香莉等, 2019) (夏杰等, 2017) (劉文彬等, 2018)。但基于整合生物學理論和骨內分泌功能, 本論文將著重探究ucOCN介導“骨?腦Crosstalk”發(fā)揮運動抗抑郁的生物學效應和可能機制, 進而深層次揭示骨內分泌活動與運動抗抑郁的分子關系, 為運動健腦提供思路和理論依據(jù)。

1 ucOCN介導“骨?腦Crosstalk”在抑郁發(fā)生中的作用機制

1.1 ucOCN調節(jié)多巴胺、γ-氨基丁酸等神經遞質

5-HT、多巴胺(Dopamine, DA)、γ-氨基丁酸(γ-aminobutyric acid, GABA)等單胺類神經遞質快速再攝取和抑制降解改善腦區(qū)突觸間隙信息傳遞, 調控抑郁發(fā)生及其遺傳易感性(Andolina et al., 2014)。5-HT濃度快速升高后, 與5-HT1B受體相互作用的鈣結合蛋白p11在海馬扣帶回中表達下調,而5-HT特異性再攝取抑制劑——SSRIs干預后, 其在海馬扣帶回表達上調, 介導抗抑郁(Wolf et al., 2018)。SSRIs還可抑制5-HT轉運體(5-Hydroxytamine transporter, SERT)表達及功能, 提高突觸間隙5-HT水平來發(fā)揮抗抑郁作用(Baudry et al., 2010)。隨著研究深入, 除經典5-HT外, 學者們開始關注谷氨酸能和DA能遞質系統(tǒng)在抑郁發(fā)生中的作用。臨床研究證實, 抗抑郁藥物可降低抑郁癥患者血清中升高的谷氨酸(Zhang et al., 2013)。而動物研究發(fā)現(xiàn), 抑郁小鼠海馬釋放的谷氨酸顯著增加(Ding et al., 2017)。氯胺酮作為非競爭性N-甲基-D-天冬氨酸受體(N-Methyl-D-aspartic receptor, NMDAR)拮抗劑, 對頑固型抑郁癥患者靜脈注射亞麻醉劑量氯胺酮后可在2 h內快速產生抗抑郁作用(Zanos et al., 2019)。提示, 腦谷氨酸能遞質系統(tǒng)調控抑郁發(fā)生。進一步研究發(fā)現(xiàn), 其分子機制與以下兩方面有關：谷氨酸激活哺乳動物雷帕霉素靶蛋白(Mammalian target of rapamycin, mTOR)途徑增加前額葉皮層神經元的突觸數(shù)量; 氯胺酮下調沉默狀態(tài)NMDAR表達后抑制真核起始因子2 (Eukaryotic initiation factor 2, eEF2)激酶(CaMKIII)活性, 導致eEF2去磷酸化并促進皮層BDNF翻譯(Gu et al., 2017)。DA調控慢性應激導致的大鼠抑郁樣行為, 其機制與DA能神經元突觸傳遞被抑制, 且右側下額葉、紋狀體、海馬齒狀回等腦區(qū)DA濃度顯著降低密切相關; 而DA受體激動劑則能改善應激型大鼠的抑郁樣行為(Kowiański et al., 2018)。最近研究顯示, 人腦組織中多巴胺D1和D2受體結合增多, 而干預抑郁樣小鼠腦區(qū)兩受體結合則產生顯著抗抑郁效應(Zhao, Ying, et al., 2019)。單胺類神經遞質在介導抑郁和運動抗抑郁中的作用已被證實, 而隨著研究深入, 有學者對此假說提出異議。但是, 不可否認的是單胺類神經遞質調控抑郁發(fā)生和抗抑郁中的作用可能與其他神經生物學機制存在密切關系。

OCN經OB分泌后穿過血腦屏障, 在海馬和中腦中與神經元相結合, 促進單胺類神經遞質合成的同時抑制GABA合成, 進而改善抑郁; 且懷孕期間向OCN-/-母體小鼠注射OCN可有效預防OCN-/-后代小鼠的抑郁表征出現(xiàn)(Oury et al., 2013)。后續(xù)研究發(fā)現(xiàn), OCN發(fā)揮作用是以ucOCN的形式調控大腦發(fā)育和腦功能, 其缺失導致空間學習能力和記憶力嚴重缺陷, 加劇抑郁樣行為(Rentz et al., 2020)。磁共振掃描發(fā)現(xiàn), ucOCN-/-小鼠大腦比其同窩WT小鼠小, 海馬裂和海馬傘之間的齒狀回CA4區(qū)覆蓋區(qū)域減少30%, 并且海馬體半球間胼胝體消失(Shan et al., 2019)。而ucOCN抑制GABA合成, 導致腦和腦干中DA和NE降低20%～50%; OB上特異性敲除ucOCN后, ucOCN–/–小鼠空間學習和記憶能力顯著下降, 且出現(xiàn)焦慮和抑郁樣行為。注射外源性ucOCN后, 其穿過血腦屏障并與中腦腹側A11細胞群、海馬顳橫回和腦干中神經元結合, 促進神經遞質合成、分泌并抑制GABA合成, 從而促進學習和記憶能力及抗焦慮、抑郁作用(Liu et al., 2018)。在探究氯胺酮抗抑郁時, 發(fā)現(xiàn)ucOCN表達上調能增加前額葉皮質(Prefrontal cortex, PFC)突觸神經小體中突觸前蛋白SynapsinⅠ及突觸后致密蛋白95 (Postsynaptic density protein 95, PSD95)和谷氨酸受體1 (Glutamate receptor 1, GLuR1)表達, 改善抑郁樣行為; 靶向性注射ucOCN siRNA可降低SynapsinⅠ等突觸蛋白表達, 抑制氯胺酮的抗抑郁作用(aan het Rot et al., 2010)。快感缺失作為抑郁癥典型癥狀, 是大腦獎賞系統(tǒng)功能障礙的直接體現(xiàn), 其大腦的中腦腹側被蓋區(qū)(Ventral tegmental area, VTA)內DA能神經的放電頻率明顯增加, ucOCN穿過血腦屏障進入VTA后降低DA能神經元放電頻率, 通過“骨?腦Crosstalk”來改善抑郁表征(Krishnan et al., 2007)。

ucOCN可通過調節(jié)神經遞質基因表達來改善抑郁。如ucOCN下調NMDA后促進谷氨酸受體AMPAR表達, 抑制CaMKIII活性, 導致eEF2去磷酸化并上調皮層中BDNF表達, 促進谷氨酸產生, 減少抑制性神經遞質GABA表達, 發(fā)揮“骨?腦Crosstalk”快速抗抑郁作用(周嬋娟, 2016)。后續(xù)研究發(fā)現(xiàn), 骨源性ucOCN通過血液途徑穿過血腦屏障后與海馬CA3區(qū)神經元膜上Gpr158結合, 作用于長鏈非編碼RNA漿細胞瘤變體易位基因1 (Long-chain non-coding RNA plasmacytic variant transposable gene 1, PVT1)表達來實現(xiàn)“骨?腦Crosstalk”調控抑郁, 當Gpr158活化后可激活IP3Rs和靶基因BDNF表達, 進而促進神經遞質表達, 改善抑郁(Khrimian et al., 2017)。慢性應激壓力亦可導致前額葉皮層(Prefrontal cortex, PFC)中Gpr158表達上調, 通過調節(jié)改變AMPA受體活性的突觸強度來誘導抑郁樣行為(Sutton et al., 2018)。在此通路中, Gpr158被證實是ucOCN的腦神經元靶受體, 且ucOCN和Gpr158在調控抑郁發(fā)生中的作用關系已被發(fā)現(xiàn)和證實。

1.2 ucOCN調節(jié)神經內分泌

神經內分泌是調控抑郁癥發(fā)生的主因之一。研究顯示, 抑郁癥小鼠血清糖皮質激素(Glucocorticoid, GC)和促腎上腺皮質激素釋放激素(Corticotropin releasing hormone, CRH)均顯著升高, 且正常小鼠長期注射GC和/或CRH均會出現(xiàn)抑郁樣行為(Edvinsson et al., 2020)?；诖? 學者們開始關注HPA軸在抑郁發(fā)生中的作用。該軸在長期慢性應激下會反復持續(xù)被激活, 導致GC、促腎上腺皮質激素(Adrenocorticotropic hormone, ACTH)和皮質醇等分泌異常, 而過量GC、ACTH等通過激活其受體可抑制小鼠海馬齒狀回顆粒下區(qū)(Subgranular zone, SGZ)神經干細胞的增殖并導致海馬萎縮(Rubin et al., 1987)。這也揭示了抑郁癥患者腦內海馬組織體積萎縮的機制。并且, HPA軸異常導致腦神經元細胞喪失、樹突萎縮、可塑性受損, 降低海馬對HPA軸的負反饋調節(jié)(Eyre & Baune, 2012)。在探究胰島素與抑郁的發(fā)生關系時, 發(fā)現(xiàn)胰島素敏感性改變激活免疫炎癥網(wǎng)絡, 損傷神經元或神經膠質細胞, 降低大腦皮質興奮(Mcintyre et al., 2007); 胰島素抑制大腦NE再攝取, 逆向抑制下丘腦兒茶酚胺和海馬中磷酸肌醇表達, 抑制NE和DA轉運蛋白, 鋰鹽代謝失衡, 導致抑郁發(fā)生(周嬋娟, 2016; Gould & Manji, 2005)。

骨中ucOCN通過血液循環(huán)作用于腎上腺皮質束狀帶細胞內質網(wǎng), 導致小鼠血清GC濃度降低, 而敲除ucOCN后GC長期處于較高水平并引發(fā)抑郁表現(xiàn)(Mar et al., 2020)。另一研究中, 抑郁癥患者血清ucOCN濃度升高的同時伴隨GC分泌異常(Eyre & Baune, 2012)。ucOCN抑制GC合成、分泌, 進而抑制前額葉皮層和海馬區(qū)核轉錄因子- κB (Nuclear factor kappa-B, NF-κB)途徑, 小鼠抑郁樣行為被改善(Edvinsson et al., 2020)。并且, 在探究ucOCN調控抑郁發(fā)生機制時, 發(fā)現(xiàn)抑郁癥患者血清ucOCN表達下調激活HPA軸, 導致ACTH和皮質醇濃度異常升高(Rubin et al., 1987)。而GC、ACTH和皮質醇分泌異常導致腦部神經元受損、可塑性下降, 抑制海馬對HPA軸的負反饋調節(jié)(Eyre & Baune, 2012)。GPRC6A是ucOCN在腦內海馬、扣帶回、齒狀回等和胰腺b細胞中的靶受體, 敲除ucOCN后, GPRC6A失活會抑制小鼠胰島素分泌產生(de Toni et al., 2019); 臨床研究亦發(fā)現(xiàn), 2型糖尿病(Type 2 diabetes mellitus, T2DM)患者血清ucOCN與胰島素分泌呈顯著正相關(Liang et al., 2016)。T2DM小鼠血清ucOCN下降導致抑郁樣行為出現(xiàn), 而外源性ucOCN可顯著改善ucOCN-/-小鼠的抑郁行為。其分子機制與胰島素分泌減少激活海馬炎癥反應和提高IR水平, 導致Ca2+通道被抑制并下調膜蛋白Ezrin表達, 引起小膠質細胞、星型膠質細胞等功能失常和神經元細胞受損、死亡有關(牛望等, 2020)。綜上所述, 抑郁發(fā)生與骨源性ucOCN介導的胰島素信號途徑密切相關, 并且這在一定程度上也揭示了T2DM共病抑郁癥發(fā)生的分子機制。

1.3 ucOCN介導神經免疫機制

抑郁發(fā)生與壓力應激和T淋巴細胞、B淋巴細胞、自然殺傷細胞(Natural killer cell, NK)等免疫細胞數(shù)量和活性降低, 促炎因子[腫瘤壞死因子- α (Tumor necrosis factor-α, TNF-α)、白介素6 (Interleukin-6, IL-6)等]釋放等多種免疫功能異常密切相關。應激狀態(tài)下, CRH增加、交感神經系統(tǒng)和HPA軸激活引起皮質醇等激素釋放, 抑制正常免疫反應(胡亮等, 2019)。近幾年, 神經免疫在抑郁發(fā)生中的作用機制受到重點關注。研究表明, 神經炎癥通過調控神經再生、HPA軸功能等來影響抑郁和抑郁樣神經病變發(fā)生。IL-10作為抗炎因子, 其介導抑郁發(fā)生, 當對抑郁大鼠注射IL-10后可顯著改善其神經功能; 同時, 海馬中IL-1β和TNF-α表達下調, 實質中積聚的中性粒細胞數(shù)量減少, 神經保護增強(Knoblach & Faden, 1998)。人體研究發(fā)現(xiàn), 抑郁發(fā)生后T細胞募集, 通過對抑郁癥患者腦組織分析, 發(fā)現(xiàn)海馬區(qū)CD3+、CD4+T淋巴細胞高表達, 而75%樣本中存在CD8+T淋巴細胞高表達(Holmin et al., 1998)。但該研究樣本數(shù)量僅9例, 結果存在一定局限性。有研究卻發(fā)現(xiàn), 少突膠質細胞、小膠質細胞和星型膠質細胞等在神經系統(tǒng)中均可形成補體, 抑郁發(fā)生后募集活化的T淋巴細胞、巨噬細胞和中性粒細胞等來合成和分泌補體蛋白(Woodruff et al., 2010; Hansen & Malcangio, 2013)。小膠質細胞激活補體受體3 (Complement receptor 3, CR3)在抑郁神經系統(tǒng)病變中發(fā)揮突觸修剪作用(Kettenmann et al., 2013)。小膠質細胞激活CR3后引起海馬長時程突觸抑制, 在神經炎癥導致抑郁等相關腦功能障礙中導致突觸損壞及記憶損傷(Zhang et al., 2014)。LIAN等發(fā)現(xiàn), 神經炎癥因子NF-κB激活星型膠質細胞補體C3來參與抑郁發(fā)生(Lian et al., 2015)。并且, NF-κB激活后促進小膠質細胞釋放C3, 并作用于神經細胞上C3受體引起突觸功能改變; 此外, NF-κB/C3/C3aR途徑還參與神經細胞內鈣電流調節(jié), 增強興奮狀態(tài)下突觸后電流。然而, 突觸后電流受AMPAR調節(jié), 介導抑郁的突觸重塑(丘玥等, 2016)。表明, 神經系統(tǒng)自身合成補體參與抑郁的發(fā)生、發(fā)展。抑郁發(fā)生還與IL-1等細胞因子透過血腦屏障刺激脈絡叢和第四腦室周圍丘腦、下丘腦、海馬、室旁核等器官組織中白細胞增多, 進而引起的免疫反應有關。

mTOR是調節(jié)免疫反應的關鍵因子, 可通過調控APP剪切酶如：淀粉蛋白前β位分解酶1 (β-site APP-cleaving enzyme l, BACE1)、Disintegrin和金屬蛋白酶結構域15 (Metalloproteinase domain 15, ADAM15)表達來維持海馬突觸可塑性和記憶形成的關鍵因子, 而阻斷ucOCN介導的絲氨酸/蘇氨酸激酶(Serine/threonine kinase, AKT)/mTOR/ NF-κB途徑后, ucOCN調控抑郁發(fā)生的作用消失(Stepanichev et al., 2014)。星型膠質細胞是一種神經元功能輔助細胞, 參與炎癥反應, 抑郁發(fā)生后星型膠質細胞數(shù)量和密度減少、形態(tài)萎縮(Halassa et al., 2009; Jun et al., 2014)。在探究不同濃度ucOCN對C57BL/6乳鼠星型膠質細胞增殖影響時,發(fā)現(xiàn)相較于其它濃度, 30 ng/mL ucOCN可顯著上調CyclinD2、D3、E及B1表達, 促進G1和G1/S期星型膠質細胞增殖(王新發(fā), 2017)。然而, ucOCN功能缺失導致星型膠質細胞能量代謝紊亂,三磷酸腺苷(Adenosine triphosphate, ATP)不能正常合成, 缺乏肌醇1, 4, 5-三磷酸受體2型(Inositol 1, 4, 5-trisphosphate receptors 2, IP3Rs2)和轉基因阻滯的囊泡膠質細胞誘導星型膠質細胞ATP釋放缺陷, 而補充ATP可刺激星型膠質細胞的內源性ATP釋放在小鼠抑郁癥模型中誘導抗抑郁樣效應, 進而在內側PFC中的三磷酸腺苷受體(Adenosine Triphosphate Receptor, P2X2)受體介導ATP的抗抑郁樣作用(Liu et al., 2004)。并且, 星型膠質細胞通過局部K+攝取和空間K+緩沖星型膠質細胞阻止細胞外K+的積累以及興奮性氨基酸轉運蛋白1 (Excitatory amino acid transporter 1, EAAT1)、EAAT2 Na+依賴轉運蛋白的谷氨酸積累, 從而影響抑郁的神經元興奮性(Stepanichev et al., 2014)。另外, ucOCN也可通過調節(jié)神經免疫相關基因表達來調節(jié)抑郁。ucOCN可上調海馬組織中PVT1表達, 降低TNF-α、IL-1β和IL-6表達后通過作用于海馬組織蛋白激酶C (Protein kinase C, PKC)進而上調BDNF表達, 促進神經元再生及星型膠質細胞活化, 減少TUNEL陽性細胞數(shù)量(Zhao, Ding, et al., 2019); 亦可激活AKT/mTOR炎癥途徑從而調節(jié)AKT等蛋白表達, 促進星型膠質細胞、小膠質細胞增加并抑制神經元細胞凋亡, 改善抑郁樣行為。并且, 體外實驗也證實, ucOCN對Aβ-42損傷PC12細胞的保護作用是通過AKT/mTOR途徑進行調控(單暢, 2019)。以上直接證據(jù)表明, 骨源性ucOCN通過介導AKT/mTOR/NF-κB炎癥途徑和炎癥細胞來調節(jié)海馬扣帶回星型膠質細胞功能, 進而調控抑郁發(fā)生。然而, ucOCN也可直接作用于IL-6、IL-10、IL-1β等表達(Millar et al., 2019), 并通過影響HPA軸、中性粒細胞數(shù)量等來調控抑郁發(fā)生, 那么ucOCN能否通過介導IL-6、IL-10等炎癥因子進而調控抑郁發(fā)生尚值得后續(xù)探究。

1.4 ucOCN調節(jié)神經再生

重度抑郁癥患者的腦成像發(fā)現(xiàn), 海馬齒狀回(Dentate gyrus, DG)等腦組織微細結構退化和海馬體積變小, 這一研究驗證了中樞神經結構退化在抑郁發(fā)生中的作用, 也催生了“抑郁癥神經再生假說” (Bremner et al., 1995)。中樞側腦室室管膜下區(qū)(Subventricular, SVZ)和海馬DG顆粒下層區(qū)是目前研究證實的兩個存在神經前體細胞和具有神經再生潛能的區(qū)域(石旺清等, 2013)。海馬神經再生障礙是抑郁發(fā)生的重要機制, 調控海馬神經功能及促進神經干細胞增殖、分化、成熟后整合參與神經環(huán)路可抗抑郁或改善抑郁樣行為(Santarelli et al., 2003)。后續(xù)研究發(fā)現(xiàn), 海馬為主的齒狀回顆粒下層區(qū)神經發(fā)生減退被認為是抑郁發(fā)生的最終通路(Duman, 2004)。慢性應激是抑郁發(fā)生的誘導因素, 動物研究中, 社交失敗等應激源抑制神經發(fā)生, 而抗抑郁可促進海馬神經再生(郭雨欣等, 2012)。但有研究卻發(fā)現(xiàn), 抑制神經發(fā)生并不能導致抑郁發(fā)生。習得性無助抑郁模型的腦室壁下回神經發(fā)生減退與抑郁行為表現(xiàn)并不相關(Vollmayr et al., 2003); 經顱磁治療可逆轉應激對抑郁癥大鼠HPA軸的影響, 但對中側腦室神經元發(fā)生作用不顯著(Czéh et al., 2002); 并且, 阻斷神經發(fā)生后, 單胺類抗抑郁藥物、ACTH釋放因子和血管升壓素藥物的效果不受影響(David et al., 2009)。在一項臨床研究中, 發(fā)現(xiàn)抗抑郁藥物對情緒的改善作用并不依賴于神經再生(Bessa et al., 2009)。神經干細胞主要存在于中側腦室壁的腦室下區(qū)和海馬齒狀回顆粒下層, 以上研究發(fā)現(xiàn)海馬區(qū)神經再生是調控抑郁的關鍵, 而中側腦室壁的腦室下區(qū)的神經再生卻無效。近年來, 探究T2DM神經再生與認知障礙相關性受到國內學者關注。T2DM大鼠骨中Runx2表達下調后抑制ucOCN分泌, 進而導致中腦和海馬神經再生被抑制, 神經元結構和功能改變, 認知功能(空間探索和學習記憶能力)受損(Gu et al., 2017)。T2DM加速認知障礙及迅速發(fā)展為癡呆癥, 導致智力活動、執(zhí)行能力和處理速度下降(Yu et al., 2020)。然而, T2DM患者血清ucOCN水平顯著下降, 這是引起認知功能障礙, 甚至抑郁癥、癡呆癥及其他精神疾病的原因機制。

抑郁發(fā)生后大腦神經再生障礙會導致學習記憶能力下降等表征(López et al., 2016)。ucOCN作為骨源性特異蛋白, ucOCN–/–小鼠雙皮質素(Dipcortin, DCX)+和BrdU+神經元數(shù)量均顯著減少, 當母體基因型為ucOCN–/–時, 這種減少更為嚴重; 發(fā)現(xiàn)ucOCN的敲除促進海馬神經細胞凋亡, 減緩神經發(fā)生是成年抑郁樣小鼠海馬依賴性學習能力下降的主因(Oury et al., 2015)。ucOCN基因敲除導致的神經元數(shù)量減少、再生能力下降是導致抑郁發(fā)生的主因。其分子機制與骨中ucOCN表達下調入血后抑制海馬齒狀回Notch途徑(袁萍, 2020)和磷酸二酯酶9 (Phosphodiesterase 9, PDE9)-環(huán)磷酸鳥苷(Cyclic guanosine phosphate, cGMP)-cGMP依賴性蛋白激酶(cGMP dependent protein kinase, PKG)途徑(校歡, 2020)密切相關。兩條信號途徑被抑制后下調靶基因BDNF等表達, 導致小鼠海馬齒狀回中BrdU、DCX和BrdU/NeuN陽性細胞數(shù)量下降, 并顯著抑制NSCs細胞活力及其增殖, 導致抑郁發(fā)生, 實現(xiàn)“骨?腦Crosstalk”, 上述機制匯總可見表1。

2 ucOCN介導“骨?腦Crosstalk”在運動抗抑郁中的作用機制

2.1 ucOCN調節(jié)神經遞質在運動抗抑郁中的作用

整合生理學的觀點認為, 機體各器官組織之間是相互作用、影響。骨既是運動器官, 亦是重要代謝器官, 因此運動抗抑郁的積極效應均可從骨中找到答案。運動抗抑郁中單胺類神經遞質分泌增加(Lee et al., 2019)。有研究發(fā)現(xiàn), 慢性中等不可預知應激抑郁大鼠不同腦區(qū)內單胺類神經遞質(如NE、DA、5-HT和5-羥吲哚乙酸)水平顯著下降, 而長期游泳訓練在改善大鼠抑郁表征的同時也會顯著恢復和增加單胺類神經遞質的分泌(崔冬雪, 2005)?；诖x組學分析, 不同運動促進CUMS抑郁模型大鼠血漿中5-HT、NE、DA等分泌從而改善抑郁(張波, 2019)。而ucOCN是力學刺激敏感基因, 運動促進骨中ucOCN表達并進而調控抑郁改善, 臨床研究中, 每周3～5次、每次35min的慢跑有氧運動使得成年抑郁癥患者血清GABA含量下降且谷氨酸含量升高, 進而改善抑郁樣行為; 并且, 血清ucOCN濃度升高與GABA濃度下降和谷氨酸濃度升高呈顯著正相關(杜遠, 2019)。表明, 運動促進抑郁癥患者血清ucOCN高表達同時亦抑制GABA并促進谷氨酸等神經遞質分泌, 改善抑郁樣行為。隨著對ucOCN研究深入, 發(fā)現(xiàn)運動上調抑郁癥大鼠骨中ucOCN表達并促進血清5-HT、DA分泌, 從而改善其抑郁樣行為(Zoch et al., 2016)。Obri等(2018)研究也發(fā)現(xiàn), 8周跑臺訓練上調CUMS大鼠骨中ucOCN表達并釋放入血后, 促進5-HT并抑制GABA等分泌, 從而改善其抑郁樣行為。另外, 2個月跑臺訓練(30min/天)可顯著提高T2DM合并抑郁癥小鼠血清ucOCN水平, 改善其抑郁樣行為(Rentz et al., 2020)。其機制與運動激活ucOCN及其介導Gpr158/BDNF途徑, 促進神經遞質分泌, 進而調控抑郁等認知障礙發(fā)生密切相關。提示, ucOCN介導的單胺類神經遞質分泌實現(xiàn)了“骨?腦Crosstalk”從而介導運動抗抑郁?；诠侵衭cOCN介導抗抑郁的作用及其運動敏感性, 運動誘導骨中ucOCN表達或激活后, 促進單胺類神經遞質分泌進而抗抑郁的機制與ucOCN促進IL-6表達及激活胰島素?胰島素受體途徑有關, IL-6及胰島素分泌增加經過血液循環(huán)、血腦屏障進入腦組織促進5-HT、DA并抑制GABA等單胺類神經遞質分泌, 進而改善抑郁(Fordahl & Jones, 2017; Muhammad et al., 2013)。

表1 ucOCN介導“骨?腦Crosstalk”在抑郁發(fā)生中的作用機制匯總表

注：羧化不全骨鈣素(ucOCN), 血清糖皮質激素(GC), 下丘腦?垂體?腎上腺軸(HPA軸), 促腎上腺皮質激素(ACTH), G蛋白偶聯(lián)受體C家族A成員6(GPRC6A), 胰島素抵抗(IR), 促腎上腺皮質激素釋放激素(CRH), 核轉錄因子-κB (NF-κB), 星形膠質細胞補體C3, 谷氨酸受體AMPAR受體, 肌醇1, 4, 5-三磷酸受體2型(IP3Rs2), 三磷酸腺苷受體(P2X2), 5-HT轉運體基因連鎖多態(tài)性區(qū)域(5-HTTLPR), N-甲基-D-天冬氨酸(NMDA)。

2.2 ucOCN調節(jié)神經內分泌在運動抗抑郁中的作用

神經內分泌介導抑郁發(fā)生和減緩, 而運動作為一種應激反應可激活HPA軸促進GC、ACTH等激素分泌, 同時亦可增加HPA軸對慢性應激的適應(Hegberg et al., 2019)。Pang等(2013a)在研究體育鍛煉對酒精戒斷康復期間的抑郁樣行為影響時, 發(fā)現(xiàn)6周自主跑輪運動可顯著改善酒精戒斷康復期間小鼠的抑郁樣行為; 后續(xù), Pang等利用游泳訓練(6周、6天/周、每次50 min)對該小鼠進行運動干預, 發(fā)現(xiàn)酒精戒斷康復階段小鼠HPA軸被激活, 血清中ACTH、GC、CRH和促視神經黑皮質激素分泌增加, 小鼠抑郁行為得到顯著改善(Pang et al., 2013b)。HPA軸調控抑郁發(fā)生、改善, 4周跑輪運動加快小鼠在約束壓力下皮質醇、ACTH、鹽皮質激素到達峰值時間及加快其衰減; 自主跑輪運動改善全身性注射地塞米松引起的腎上腺變小和ACTH、GC、皮質醇降低, 進而改善抑郁(Hare et al., 2014)。臨床研究中, 對80名肥胖青少年進行3個月有氧運動減肥同時, 發(fā)現(xiàn)肥胖青少年血清ucOCN水平與尿皮質醇和抑郁樣行為改善呈顯著正相關(Okbay Güne? et al., 2017)。6周有氧運動訓練可顯著激活重度抑郁癥患者HPA軸, 提高血清皮質醇濃度, 改善抑郁(Gerber et al., 2020)。而對接受過乳腺癌手術且伴有抑郁樣行為的85名女性進行6個月運動干預后, 發(fā)現(xiàn)HPA軸功能顯著改善, 唾液皮質醇顯著增加, 且伴隨總白細胞、中性粒細胞和淋巴細胞等顯著下降(Saxton et al., 2014)。以上動物和臨床研究均提示, 運動通過激活HPA軸, 促進ACTH、GC、鹽皮質激素、皮質醇等分泌進而改善抑郁行為。其機制與心鈉素(Atrial natriuretic peptide, ANP)受體、GC受體、鹽皮質激素受體等mRNA表達增加密切相關。ucOCN介導抑郁且在運動應激下表達顯著上調, 其表達上調后促進ACTH、GC和鹽皮質激素分泌, 血清濃度增加(Nella et al., 2016); 亦可激活HPA軸功能, 提高血清皮質醇、ACTH濃度(Shobana et al., 2019)。而17名抑郁癥患者進行12周跑步訓練后, 血清ucOCN顯著升高且GC、鹽皮質激素和ACTH濃度亦顯著升高(Tsikirai et al., 2020); 但也有研究發(fā)現(xiàn), 12周跑步運動不能顯著提高肺癌患者血清ucOCN和GC、ACTH等濃度, 抑郁樣行為變化不明顯(Cavalheri et al., 2019)。以上結果差異, 說明運動在上調抑郁癥患者ucOCN表達及GC等相關激素分泌上存在時間差異, 并與被試對象不同有關?，F(xiàn)有研究證實ucOCN介導ACTH、GC、HPA軸等實現(xiàn)了運動抗抑郁中的“骨?腦Crosstalk”, 但目前運動方式單一, 多種運動抗抑郁作用的對比或聯(lián)合干預研究尚待補充。

2.3 ucOCN介導神經免疫機制在運動抗抑郁中的作用

神經免疫可直接參與運動抗抑郁, 亦可介導HPA軸等神經內分泌來發(fā)揮作用, 由此其在運動抗抑郁中的作用得到特別關注(胡亮等, 2019)。近年來, 運動抗抑郁的神經免疫機制集中在：細胞或體液免疫介導氧化應激或炎癥反應進而改善抑郁行為上(Kohut et al., 2006)。如有氧跑臺運動可通過誘導內源性硫化氫(Hydrogen sulfide, H2S)氣體信號, 并通過抑制Toll樣受體4 (Toll-like receptors 4, TLR4)介導的髓樣分化因子(Myeloid differentiation factor 88, MyD88)/NF-кB炎癥信號途徑, 從而改善慢性不可預知應激(CUMS)抑郁小鼠抑郁樣行為, 促進海馬神經元修復; 并且TLR4抑制劑的效果與跑臺運動效果一致, 均可抑制抑郁小鼠血液與海馬組織炎癥反應(屈紅林, 2019)。Kohut等發(fā)現(xiàn), 有氧運動通過降低血清中IL-6、IL-18、TNF-α、C-反應蛋白(C-reactive protein, CRP)等炎癥因子來改善慢性應激引發(fā)的抑郁(Eyre et al., 2013)。6次/周、共18周的自行車運動可顯著降低血清IL-6和IL-18水平(Zhao et al., 2016); 12周慢跑亦可顯著抑制慢性堵塞性肺疾病(Chronic obstructive pulmonary disease, COPD)合并抑郁癥患者血清中TNF-α、IL-4、IL-6和CRP炎癥因子水平(ABD EL-KADER & Al-Jiffri, 2016), 進而改善抑郁樣行為。動物研究中, Algaidi等(2019)利用2周強迫游泳建立抑郁癥Wistar大鼠模型, 3周自主跑輪運動干預后利用免疫組化對大鼠齒狀回、內側前額葉皮層等部位的巨噬細胞遷移抑制因子(Macrophage migration inhibitory factor, MIF)、IL-6和BDNF表達進行檢測, 發(fā)現(xiàn)MIF和IL-6表達下調后, 靶基因BDNF等激活并改善大鼠抑郁樣行為。說明, 運動改善抑郁與炎癥因子表達下調顯著相關, 但以上研究集中在有氧運動, 而抗阻訓練或有氧運動聯(lián)合抗阻訓練在改善抑郁上的作用效果尚不清楚。ucOCN介導神經免疫調節(jié)抑郁發(fā)生和減緩, 體育科學領域內, 運動通過提高OB活性來上調ucOCN表達, 進而抑制IL-6、IL-18和TNF-α等炎癥因子的mRNA表達, 可顯著改善抑郁樣行為(Napoli et al., 2014)。其機制與ucOCN表達上調可通過激活ERK途徑和STAT途徑來下調海馬中IL-6和IL-8mRNA及蛋白表達, 進而通過丙二醛(Malondialdehyde, MDA)/超氧化物歧化酶(Superoxide dismutase, SOD)/核因子類紅細胞衍生的2-樣2 (Nuclear factor erythroid- derived 2-like 2, Nrf2)/血紅素加氧酶1 (Heme oxygenase 1, HO1)途徑上調VGF和BDNF表達密切相關(Millar et al., 2020)。當利用8周有氧運動對伴隨有抑郁表現(xiàn)的大學生進行干預時, 發(fā)現(xiàn)血清中表達上調的ucOCN與下調的TNF-α和CRP呈顯著負相關, 且其抑郁行為被顯著改善(Huang et al., 2020; 許靜等, 2016)。以上研究揭示, ucOCN通過調控腦組織神經免疫實現(xiàn)了“骨?腦Crosstalk”, 從而介導運動抗抑郁。

ucOCN介導神經免疫實現(xiàn)“骨?腦Crosstalk”發(fā)揮運動抗抑郁, 其機制與ucOCN介導的PFC抗炎能力激活神經生長因子(Nerve growth factor, NGF)?酪氨酸蛋白激酶A (Tyrosine protein kinase A, TrkA) (崔建梅等, 2020)、過氧化物酶體增殖物激活受體-γ共激活因子-1α (Peroxisome proliferator- activated receptorγcoactivator-1α, PGC-1α)/Ⅲ型纖連蛋白域蛋白5 (type Ⅲ domain-containing protein 5, FNDC5)/BDNF (陳蓉, 2019)、miRNAs/ PGC-1α/賴氨酸乙酰轉移酶(Lysine Acetyltransferase, KATs) (羅佳, 2019)等信號途徑調控抑郁發(fā)生、改善密切相關。而ucOCN作為力學刺激敏感基因, 運動上調ucOCN表達后可下調抑郁小鼠海馬中IL-6、PGC-1α、miRNA-130b等mRNA表達進而調控抑郁。

圖1 ucOCN介導“骨?腦Crosstalk”在運動抗抑郁中的作用機制示意圖

注：ucOCN是OB中分化的特異性蛋白。神經元5-羥色胺(5-HT), 腦源性神經營養(yǎng)因子(BDNF), 多巴胺(DA)、γ-氨基丁酸(GABA), 糖皮質激素(GC), 促腎上腺皮質激素釋放激素(CRH), 巨噬細胞遷移抑制因子(MIF), C-反應蛋白(CRP), 白介素6 (IL-6), 腫瘤壞死因子-α (TNF-α)。運動促進骨中ucOCN表達, 通過血腦屏障入腦后, 作用于腦中海馬、前額葉等腦區(qū), 促進BDNF、DA、5-HT、NE, 抑制GABA等神經遞質表達, 同時減少IL-6水平; ucOCN通過作用于下丘腦等腦區(qū)來激活HPA軸, 促進ACTH、CRH等基因表達, 同時通過神經內分泌循環(huán)作用降低炎癥因子水平, 減緩神經炎癥反應。

3 小結與展望

ucOCN作為骨源性力學刺激敏感基因, 運動上調骨中ucOCN表達或活性, 以轉錄輔激活作用調節(jié)單胺類神經遞質分泌、神經內分泌功能和神經免疫等, 進而通過多種途徑作用于海馬等腦組織, 以“骨?腦Crosstalk”形式改善HPA軸功能、減緩中樞炎癥反應、促進神經元細胞再生, 進而發(fā)揮抗抑郁效應?；谀壳跋嚓P研究, 對ucOCN介導的“骨?腦Crosstalk” “對話”模式進行分析, 提出了運動抗抑郁中的ucOCN介導途徑, 部分機制如圖1所示。雖然綜述目前相關研究, 發(fā)現(xiàn)了“骨?腦Crosstalk”的有利證據(jù), 但仍存在幾個問題亟待進一步的探究：(1) ucOCN介導單胺類神經遞質或神經內分泌進而調控運動抗抑郁的具體分子機制網(wǎng)絡尚待揭示。(2)運動促進神經再生, ucOCN能否介導神經再生從而介導運動抗抑郁？(3)骨骼分泌物或特異性表達因子較多, 目前僅確認了ucOCN在運動抗抑郁中的作用, 未來研究需要進一步篩選可能透過血腦屏障進入腦組織發(fā)揮作用的骨分泌或表達特異性小分子物質; 或進一步探討血腦屏障上的相應受體, 并探討其機制。(4)運動激活骨中多種基因表達, 但研究發(fā)現(xiàn)可介導“骨?腦Crosstalk”的基因并不多。相信, 深入探究和驗證以上問題, 將從“骨?腦Crosstalk”的視角上更深層次的解析運動抗抑郁及運動健腦的生物學機制網(wǎng)絡。

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The potential role of bone-derived factor ucOCN in the anti-depressive effects of exercise

CHEN XiangHe1, LI WenXiu1, LIU Bo1, YIN RongBin2

(1College of Physical Education, Yangzhou University, Yangzhou 225127, China)(2College of Physical Education, Soochow University, Suzhou 215000, China)

Undercarboxylated osteocalcin (ucOCN) is a specific protein secreted by osteoblasts in bone. It has attracted attention in the field of neuroscience because of its important role in regulating neurodevelopment and neuroplasticity. “Bone-Brain Crosstalk” is a bone endocrine-nerve mediated response system. ucOCN modulate the monoamine neurotransmitters, neuroendocrine, neuroimmunity, nerve regeneration and gene expression after passing through the blood-brain barrier. ucOCN further acts on the hippocampus CA3 area, cingulate gyrus and other brain areas to regulate the occurrence and reduction of depression. As a bone-derived mechanical stimulation sensitive gene, ucOCN enters the blood circulation after exercise upregulating its expression, and mediates 5-HT/GABA secretion, HPA axis function, inflammation, neurotrophic factor (BDNF, etc.) expression or signal pathways (such as GSK3β/β-catenin, TLR4/miR- 223/NLRP3, etc.) activation to achieve the “Bone-mediated brain” and mediate the antidepressant effect of exercise. This review emphasized the anti-depression effect of exercise through the discussion and sorting out of the mechanism of ucOCN-mediated brain function changes. On one hand, it is helpful to have a deeper understanding of bone endocrine function, on the other hand, it provides a new theoretical basis and research ideas for the occurrence and improvement of depression and the study of exercise anti-depression.

undercarboxylated osteocalcin, bone, brain, exercise, depression

B845

2021-04-28

* 國家社會科學基金教育學青年課題《精準運動改善青少年抑郁癥的模式構建及應用研究》(CLA200279)。

陳祥和, E-mail: huashixh@163.com