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      調(diào)控成骨細(xì)胞分化的信號(hào)通路及細(xì)胞因子研究進(jìn)展

      2021-05-08 03:33:57趙銳王譯晗朱悅陶琳單軍
      關(guān)鍵詞:信號(hào)通路

      趙銳 王譯晗 朱悅 陶琳 單軍

      【摘要】 骨質(zhì)疏松癥是臨床常見的代謝性骨病。骨質(zhì)疏松的發(fā)生是由各種原因?qū)е碌某晒羌?xì)胞介導(dǎo)的骨生成減少或破骨細(xì)胞介導(dǎo)的骨吸收增加。骨生成作用主要由成熟的成骨細(xì)胞完成,成骨細(xì)胞主要來源于間充質(zhì)干細(xì)胞(mesenchymal stem cells,MSCs),在一系列信號(hào)通路及細(xì)胞因子等的調(diào)控下,MSCs可以分化為成骨細(xì)胞,進(jìn)而發(fā)揮骨生成作用。因此增強(qiáng)成骨細(xì)胞的分化能力至關(guān)重要。目前已知多條信號(hào)通路參與到MSCs向成骨細(xì)胞分化的過程中,例如Wnt/β-catenin、BMP-Smads、Hedgehog、Notch、PI3K/AKT、MAPKs信號(hào)通路等,同時(shí)Runx2、Osterix或PPARγ等關(guān)鍵轉(zhuǎn)錄因子也在成骨分化過程中起到重要調(diào)控作用,這些信號(hào)通路與轉(zhuǎn)錄因子的激活或抑制影響著MSCs向成骨細(xì)胞或脂肪細(xì)胞的分化傾向,但這些信號(hào)通路與轉(zhuǎn)錄因子之間是否存在相互聯(lián)系,以及它們是如何協(xié)同發(fā)揮調(diào)控成骨細(xì)胞分化的作用目前尚不明確。因此,本文針對成骨細(xì)胞分化相關(guān)重要信號(hào)通路以及轉(zhuǎn)錄因子研究進(jìn)展做一綜述,為臨床上大量的骨代謝異常相關(guān)疾病尋找發(fā)病機(jī)制以及治療靶點(diǎn)。

      【關(guān)鍵詞】 成骨分化 信號(hào)通路 Runx2 Osterix

      Advances in Signaling Pathways and Cytokines Regulating Osteoblastic Differentiation/ZHAO Rui, WANG Yihan, ZHU Yue, TAO Lin, SHAN Jun. //Medical Innovation of China, 2021, 18(05): -176

      [Abstract] Osteoporosis is a common clinical metabolic osteopathy. Osteoporosis occurs due to decreasing of bone formation by osteoblasts or increasing of bone resorption by osteoclasts. Bone formation is done by mature osteoblasts, which are mainly derived from mesenchymal stem cells (MSCs). MSCs can differentiate into osteoblasts under the control of a series of signalling pathways and transcription factors. Therefore, it is important to enhance the differentiation of osteoblasts. Several signalling pathways are known to be involved in MSCs differentiation into osteoblasts, such as Wnt/β-catenin, BMP-Smads, Hedgehog, Notch, PI3K/AKT, MAPKs signalling pathways, meanwhile transcription factors such as Runx2, Osterix and PPARγ also play an important regulatory role in osteoblast differentiation. The activation or suppression of these signalling pathways and transcription factors affect tendency of MSCs differentiation into osteoblasts or fat cells, but it is not clear whether these signalling pathways and transcription factors are related to each other and how they work together to regulate osteoblast differentiation. Therefore, this paper makes a review of the important signalling pathways and transcription factors related to osteoblast differentiation, and seeks the pathogenesis and treatment targets for a large number of bone metabolic abnormality-related diseases in clinical.

      [Key words] Osteoblast differentiation Signalling pathway Runx2 Osterix

      First-authors address: Shenyang Orthopedic Hospital, Shenyang 110044, China

      doi:10.3969/j.issn.1674-4985.2021.05.043

      骨質(zhì)疏松癥是臨床常見的代謝性骨病,一般表現(xiàn)為骨量減少、骨脆性增加,進(jìn)而導(dǎo)致骨折風(fēng)險(xiǎn)增高等。成骨細(xì)胞介導(dǎo)的骨生成與破骨細(xì)胞介導(dǎo)的骨吸收之間的平衡維持著骨的穩(wěn)態(tài)[1]。骨質(zhì)疏松的發(fā)生由各種原因?qū)е逻@種平衡被打破,出現(xiàn)成骨細(xì)胞介導(dǎo)的骨生成降低或者破骨細(xì)胞介導(dǎo)的骨吸收增加。骨生成作用主要由成熟的成骨細(xì)胞完成,成骨細(xì)胞主要由間充質(zhì)干細(xì)胞(mesenchymal stem cells,MSCs)分化而來,間充質(zhì)干細(xì)胞具有可分化為成骨細(xì)胞、脂肪細(xì)胞、軟骨細(xì)胞等的能力,在一系列信號(hào)通路及細(xì)胞因子的調(diào)控下,MSCs可以分化為

      成骨細(xì)胞,并在進(jìn)一步調(diào)控下成為成熟的成骨細(xì)胞,發(fā)揮骨生成作用。因此增強(qiáng)成骨細(xì)胞的分化及成熟能力至關(guān)重要。所以,為了更好地揭示成骨細(xì)胞分化及骨形成過程的機(jī)制,迫切需要闡明這些信號(hào)通路及細(xì)胞因子是如何在成骨細(xì)胞分化過程中發(fā)揮調(diào)控作用,以期在骨質(zhì)疏松癥的治療中尋找新的藥物靶點(diǎn)。現(xiàn)對參與調(diào)控成骨細(xì)胞分化的重要信號(hào)通路及細(xì)胞因子做一綜述。

      1 參與成骨分化調(diào)控的細(xì)胞因子Runx2與Osterix

      Runx2也稱核心結(jié)合因子1(Cbfa1),屬于Runt結(jié)構(gòu)域基因家族成員之一,因?yàn)樵诔晒羌?xì)胞的分化和成熟過程中起著至關(guān)重要的作用[2-3],同時(shí)可以抑制MSCs向脂肪細(xì)胞的分化[4],所以被認(rèn)定為成骨分化過程中最重要的轉(zhuǎn)錄因子之一。體內(nèi)實(shí)驗(yàn)證實(shí),敲除Runx2基因的小鼠顯示出完全性骨生成障礙[5]。Runx2與成骨細(xì)胞中堿性磷酸酶(ALP)、骨鈣素(OCN)、Ⅰ型膠原蛋白(COLL-1)、骨脂蛋白(BSP)及骨橋蛋白(OPN)等主要成骨分化相關(guān)基因的表達(dá)密切相關(guān),因?yàn)橐陨匣虻膯?dòng)子序列中都存在成骨特異性順式元件(OSE),而Runx2能夠與之結(jié)合,從而激活這些相關(guān)基因的表達(dá)[6-7]。

      Osterix(Osx)同樣是與成骨細(xì)胞分化過程密切相關(guān)的一種轉(zhuǎn)錄因子。有研究表明,敲除小鼠Osterix基因后,小鼠體內(nèi)骨皮質(zhì)和骨小梁發(fā)育障礙,證實(shí)了Osx與Runx2同樣是成骨細(xì)胞分化過程中所必需的關(guān)鍵轉(zhuǎn)錄因子,進(jìn)一步研究發(fā)現(xiàn)Runx2基因敲除小鼠體內(nèi)的Osx同樣不表達(dá),提示Osx的表達(dá)受Runx2調(diào)控,Osx位于Runx2的下游[8]。

      2 參與成骨分化調(diào)控的信號(hào)通路

      骨形成受多種合成代謝信號(hào)通路的調(diào)節(jié),包括PI3K/AKT、Wnt/β-catenin、BMP/TGF-β/Smad、MAPK、Notch、Hedgehog等信號(hào)通路[9-12]。這些信號(hào)通路通過調(diào)控Runx2的表達(dá),進(jìn)而影響骨形成[10,13-14]。下面對重要的成骨分化相關(guān)信號(hào)通路構(gòu)成以及目前研究現(xiàn)狀做一概述。

      2.1 Wnt/β-catenin信號(hào)通路 Wnt信號(hào)通路分為經(jīng)典和非經(jīng)典信號(hào)通路。其中,經(jīng)典Wnt信號(hào)通路(即Wnt/β-catenin通路)被認(rèn)為是在成骨細(xì)胞分化過程中起到重要調(diào)控作用的信號(hào)通路之一。經(jīng)典Wnt/β-catenin信號(hào)通路由Wnt配體及其受體以及細(xì)胞內(nèi)信號(hào)分子等組成,其成員主要包括膜外Wnt蛋白(配體)、卷曲蛋白受體(frizzled receptors)、低密度脂蛋白受體相關(guān)蛋白(LRP5/6)、連環(huán)蛋白(β-catenin)、糖原合成激酶3β(GSK3β)、下游靶基因(如Runx2、Osterix等),以及其他與Wnt/β-catenin信號(hào)通路相關(guān)的因子,如Dkks(Dickkopfs)、SCF β-TrCP等。

      研究表明,當(dāng)細(xì)胞外缺乏Wnt蛋白時(shí),GSK3β以復(fù)合體形式存在,復(fù)合體形式下的GSK3β可磷酸化β-catenin,磷酸化的β-catenin會(huì)被E3泛素連接酶SCFβ-TrCP識(shí)別結(jié)合后經(jīng)由泛素蛋白酶體系統(tǒng)降解,從而降低胞質(zhì)內(nèi)β-catenin的濃度,進(jìn)而阻斷Wnt/β-catenin信號(hào)通路[15]。Wnt/β-catenin信號(hào)通路的激活需要Wnt蛋白激活細(xì)胞表面的Frizzled受體,并進(jìn)一步與LRP5/6受體結(jié)合,抑制GSK3β的活性,阻止β-catenin磷酸化,保持了β-catenin蛋白的穩(wěn)定,使未磷酸化的β-catenin轉(zhuǎn)移至細(xì)胞核內(nèi),進(jìn)而增加TCF/LEF的轉(zhuǎn)錄活性和成骨相關(guān)基因的表達(dá)。

      Wnt/β-catenin信號(hào)通路具有促進(jìn)成骨分化和抑制成脂分化的作用[16]。這種作用已在多種細(xì)胞模型中被證實(shí)。例如,在3T3-L1細(xì)胞系中,Wnt/β-catenin信號(hào)通路和成脂特異性轉(zhuǎn)錄因子過氧化物酶體增殖物激活受體γ(PPARγ)相互調(diào)節(jié)以調(diào)控細(xì)胞的成脂分化趨勢[17]。加入Wnt3a可增強(qiáng)BM-MSC和C3H10T1/2細(xì)胞的成骨分化,同時(shí)抑制向脂肪細(xì)胞的分化[18-19]。加入Dkk1,可加強(qiáng)3T3-L1細(xì)胞成脂分化效果,敲除Dkk1導(dǎo)致MSCs的成脂分化效應(yīng)降低,而MC3T3-E1細(xì)胞和BM-MSCs成骨分化效應(yīng)增強(qiáng)[17,20]。

      Wnt/β-catenin信號(hào)通路在調(diào)節(jié)成骨細(xì)胞分化及骨形成方面最終作用于Runx2,Wnt/β-catenin信號(hào)通路通過調(diào)控Runx2的表達(dá),進(jìn)而發(fā)揮Runx2調(diào)節(jié)成骨分化相關(guān)基因ALP、OCN、COLL-1、BSP及OPN等表達(dá)的作用,促進(jìn)了成骨細(xì)胞的分化與成熟。Runx2基因啟動(dòng)子序列中存在一個(gè)TCF作用元件,β-catenin通過與此作用元件進(jìn)行結(jié)合,繼而啟動(dòng)Runx2及下游靶基因的表達(dá),從而對成骨細(xì)胞分化及骨形成進(jìn)行調(diào)控[21]。

      2.2 BMP/Smads信號(hào)通路 在參與成骨細(xì)胞分化過程的眾多信號(hào)通路中,BMP/Smads信號(hào)通路是激活成骨細(xì)胞分化及骨形成十分重要的一條通路。BMPs是TGF-β超家族中的重要成員。其中BMP2、4、7、9等,在成骨細(xì)胞分化過程中起到重要的調(diào)節(jié)作用,因此被認(rèn)為是目前骨代謝領(lǐng)域的研究熱點(diǎn)之一[22],同時(shí)多數(shù)學(xué)者認(rèn)為BMPs對成骨細(xì)胞分化的調(diào)控作用更具有特異性[23]。BMP/Smads/Runx2/Osterix信號(hào)通路被認(rèn)為是介導(dǎo)成骨細(xì)胞分化最重要以及最特異性的通路之一,研究表明,BMPs通過結(jié)合細(xì)胞膜上特異性受體進(jìn)而激活BMP/Smads通路,使下游的Smads蛋白(如Smad1、5)發(fā)生磷酸化,然后進(jìn)一步啟動(dòng)成骨細(xì)胞特異性轉(zhuǎn)錄因子基因(如Runx2、Osterix等)轉(zhuǎn)錄,Runx2、Osterix繼續(xù)促進(jìn)成骨分化相關(guān)基因ALP、OCN、COLL-1、BSP及OPN等的表達(dá),從而增強(qiáng)了MSCs向成骨細(xì)胞分化及骨形成的能力[10,23]。

      泛素蛋白酶體系統(tǒng)在BMP/Smads信號(hào)通路中發(fā)揮了重要調(diào)控作用,特別是屬于E3泛素連接酶的Smurf蛋白,其中最具代表性的Smurf1,它能特異性識(shí)別和結(jié)合Runx2及Smad1,促使它們經(jīng)過泛素蛋白酶體途徑降解,進(jìn)而抑制了由BMP/Smads信號(hào)通路介導(dǎo)的成骨細(xì)胞分化及骨形成[24-25]。human MSCs(hMSCs)細(xì)胞在經(jīng)過成骨誘導(dǎo)后泛素特異性蛋白酶USP34的表達(dá)增加,敲除USP34會(huì)抑制hMSCs細(xì)胞成骨分化。選擇性敲除小鼠MSCs細(xì)胞中的USP34導(dǎo)致細(xì)胞骨形成能力下降。此外,USP34的缺失會(huì)減弱BMP2介導(dǎo)的骨分化,進(jìn)而損害骨生成能力,而進(jìn)一步敲除Smurf1恢復(fù)了USP34缺失MSCs細(xì)胞在體外的成骨潛力。證明了,USP34通過減弱Smurf1介導(dǎo)的泛素化降解Smad1和Runx2的能力,穩(wěn)定了Smad1和Runx2,進(jìn)而促進(jìn)成骨細(xì)胞分化及骨形成[26]。有研究表明,TGF-β/BMP-2信號(hào)通路是在成骨細(xì)胞分化晚期細(xì)胞成熟過程中,而非早期發(fā)揮主要作用[27]。

      由此可見,BMP/Smads通路是參與調(diào)控成骨細(xì)胞分化的重要信號(hào)通路之一,與Wnt/β-catenin信號(hào)通路類似,BMP/Smads信號(hào)通路可通過作用于Runx2、Osterix從而起到增強(qiáng)MSCs向成骨細(xì)胞分化的效果,同時(shí)其自身也受到多種因素的調(diào)節(jié),例如蛋白磷酸化、泛素化途徑等。

      2.3 Hedgehog信號(hào)通路 Hedgehog信號(hào)通路是由Hedgehog相應(yīng)配體(Ihh、Shh、Dhh)、受體(Ptc、Smo)及細(xì)胞內(nèi)信號(hào)分子(Gli)等組成。缺失Hedgehog蛋白時(shí),Ptc抑制Smo的活性;當(dāng)Hedgehog與Ptc1受體結(jié)合后,Smo受體被激活,激活的Smo進(jìn)一步激活Gli,促使它們?nèi)牒耍M(jìn)而啟動(dòng)下游靶基因的表達(dá)。

      近期研究發(fā)現(xiàn),Hedgehog信號(hào)通路主要參與促進(jìn)MSCs向成骨細(xì)胞分化,并阻止其向脂肪細(xì)胞分化[28],而且這種作用是通過調(diào)控Runx2的表達(dá)而實(shí)現(xiàn)的[2,29-31]。其中,Shh在成骨分化早期而Ihh主要在分化后期起主要作用[32-33]。研究表明,在MSCs細(xì)胞中,過表達(dá)Gli2能增強(qiáng)成骨細(xì)胞分化及礦化能力,敲除Runx2后這種促進(jìn)效果被消除[29];而在未敲除Runx2的MSCs中,通過降低Gli2的表達(dá)能顯著抑制Ihh介導(dǎo)的成骨分化,證明了Ihh及Gli2對成骨分化具有促進(jìn)作用,同時(shí)這種作用依賴于Runx2的表達(dá)增高。有研究證明Runx2對Hedgehog信號(hào)通路也存在調(diào)節(jié)作用,Runx2可以直接調(diào)節(jié)軟骨細(xì)胞、成骨前體細(xì)胞和成骨細(xì)胞中的Ihh表達(dá),同時(shí)可以影響成骨前體細(xì)胞和成骨細(xì)胞中的Gli1和Ptc1表達(dá)[34]。同時(shí)也有實(shí)驗(yàn)證明,在細(xì)胞成骨分化過程中Hedgehog信號(hào)通路的調(diào)節(jié)作用不是持續(xù)存在的,在某些成骨分化階段其他調(diào)節(jié)成骨分化信號(hào)通路發(fā)揮主導(dǎo)作用,例如Wnt通路等[31]。

      總之,Hedgehog信號(hào)通路與Wnt/β-catenin、BMP/Smads信號(hào)通路一樣具有通過調(diào)控Runx2的表達(dá)來調(diào)節(jié)成骨細(xì)胞分化及骨形成的作用,因而同樣被視作調(diào)控成骨細(xì)胞分化及骨形成的關(guān)鍵信號(hào)通路之一,但這種調(diào)控作用是由Hedgehog信號(hào)通路單獨(dú)直接調(diào)控,還是必須借助Wnt/β-catenin或BMP/Smads信號(hào)通路而協(xié)同發(fā)揮作用尚無法確定,此外,對于Hedgehog信號(hào)通路于體內(nèi)外發(fā)揮促進(jìn)成骨分化作用是否存在時(shí)限性仍有爭議。

      2.4 其他參與成骨分化的信號(hào)通路 大量實(shí)驗(yàn)證實(shí),Notch信號(hào)通路在調(diào)節(jié)MSCs向成骨細(xì)胞分化過程中起到重要作用,但得到的研究結(jié)果并不完全一致,多數(shù)研究認(rèn)為Notch信號(hào)通路發(fā)揮抑制成骨細(xì)胞分化以及降低骨量的作用[35-37]。另一方面,也有研究表明,Notch信號(hào)通路在體外具有促進(jìn)成骨細(xì)胞分化的作用,而且這種促進(jìn)效果伴隨著BMP2的表達(dá)增加[38]。PI3K/AKT信號(hào)通路在許多細(xì)胞活動(dòng)中起著重要作用,如細(xì)胞生長、增殖等[39]。最近的研究證明,PI3K/AKT信號(hào)通路在成骨分化過程中可能起到重要調(diào)控作用[40-41]。有研究表明,MAPKs家族成員JNK、ERK和p38MAPK信號(hào)通路通過調(diào)控成骨分化而影響骨骼的形成[42-43],同時(shí)p38MAPK和Prkd1信號(hào)通路參與MC3T3-E1細(xì)胞的在缺氧條件下的成骨分化[44]。

      3 調(diào)控成骨分化的細(xì)胞因子、信號(hào)通路之間的聯(lián)系

      目前認(rèn)為Runx2在成骨細(xì)胞分化的起始階段發(fā)揮主要作用,誘導(dǎo)MSCs分化為未成熟的成骨細(xì)胞。而Osx的進(jìn)一步作用導(dǎo)致成骨細(xì)胞的最終分化與成熟,Runx2作為Wnt/β-catenin信號(hào)通路下游的信號(hào)因子,而Osx是BMP-Smads信號(hào)通路下游的信號(hào)因子,有文獻(xiàn)認(rèn)為成骨分化早期Wnt/β-catenin信號(hào)通路起主要調(diào)控作用,而分化后期BMP-Smads信號(hào)通路發(fā)揮主導(dǎo)作用使成骨細(xì)胞進(jìn)一步分化成熟[45]。有研究表明,Akt可以通過增強(qiáng)Runx2的穩(wěn)定性和轉(zhuǎn)錄活性,進(jìn)而促進(jìn)BMPs介導(dǎo)的成骨分化[10],說明Akt信號(hào)通路與BMP-Smads信號(hào)通路之間存在著相互影響。多項(xiàng)研究證明,Hedgehog信號(hào)通路與BMP2發(fā)揮協(xié)同作用促進(jìn)MSCs的成骨分化[2,46]。實(shí)驗(yàn)證明,Notch信號(hào)通路發(fā)揮抑制成骨細(xì)胞分化的效果是通過降低Wnt/β-catenin信號(hào)通路活性而達(dá)到的[35],同時(shí)這種抑制效果伴隨著Runx2的表達(dá)降低,BMP信號(hào)通路可能也參與到對成骨分化抑制的調(diào)控[36],但也有文獻(xiàn)表明這種抑制分化效果是通過降低Wnt/β-catenin信號(hào)通路活性而非BMP信號(hào)通路[37]。

      綜上所述,MSCs向成骨細(xì)胞分化的調(diào)控機(jī)制十分復(fù)雜,Wnt/β-catenin、BMP-Smads、Hedgehog、Notch、PI3K/AKT、MAPKs等多條主要信號(hào)通路可以通過直接或間接作用于Runx2、Osterix或PPARγ等關(guān)鍵轉(zhuǎn)錄因子,而調(diào)節(jié)MSCs向成骨細(xì)胞或脂肪細(xì)胞的分化傾向,并且這些信號(hào)通路不是孤立存在的,它們通過作用于共同的轉(zhuǎn)錄因子,或在調(diào)控分化過程中的不同時(shí)期發(fā)揮主導(dǎo)作用而彼此相互聯(lián)系,協(xié)同參與調(diào)控成骨細(xì)胞分化。同時(shí)通過對這些成骨分化信號(hào)通路以及轉(zhuǎn)錄因子的深入研究,發(fā)現(xiàn)它們被激活或抑制的機(jī)制也十分復(fù)雜,蛋白磷酸化、蛋白泛素化途徑、長鏈非編碼RNA(long noncoding RNA,lncRNA)、微小RNA(microRNAs,miRNAs)、外泌體Exosomes(Exos)等都對成骨細(xì)胞分化信號(hào)通路以及轉(zhuǎn)錄因子有重要的調(diào)控作用。因此,還需要在現(xiàn)有研究基礎(chǔ)上,全面的、深入的針對成骨分化相關(guān)重要信號(hào)通路以及轉(zhuǎn)錄因子開展機(jī)制研究,為臨床上大量的骨代謝異常相關(guān)疾病尋找發(fā)病機(jī)制以及治療靶點(diǎn)。

      參考文獻(xiàn)

      [1] Tsuchiya H,Kitoh H,Sugiura F,et al.Chondrogenesis enhanced by overexpression of sox9 gene in mouse bone marrow-derived mesenchymal stem cells[J].Biochem Biophys Res Commun,2003,301(2):338-343.

      [2] Yamaguchi A,Komori T,Suda T.Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1[J].Endocr Rev,2000,21(4):393-411.

      [3] Komori T.Runx2, an inducer of osteoblast and chondrocyte differentiation[J].Histochem Cell Biol,2018,149(4):313-323.

      [4] Komori T.Regulation of skeletal development by the Runx family of transcription factors[J].J Cell Biochem,2005,95(3):445-453.

      [5] Komori T,Yagi H,Nomura S,et al.Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts[J].Cell,1997,89(5):755-764.

      [6] Cheng A,Genever P G.SOX9 determines Runx2 transactivity by directing intracellular degradation[J].J Bone Miner Res,2010,25(12):2680-2689.

      [7] Stein G S,Lian J B,van Wijnen A J,et al.Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression[J].Oncogene,2004,23(24):4315-4329.

      [8] Nakashima K,Zhou X,Kunkel G,et al.The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation[J].Cell,2002,108(1):17-29.

      [9] Radio N M,Doctor J S,Witt-Enderby P A.Melatonin enhances alkaline phosphatase activity in differentiating human adult mesenchymal stem cells grown in osteogenic medium via MT2 melatonin receptors and the MEK/ERK (1/2) signaling cascade[J].J Pineal Res,2006,40(4):332-342.

      [10] Choi Y H,Kim Y J,Jeong H M,et al.Akt enhances Runx2 protein stability by regulating Smurf2 function during osteoblast differentiation[J].FEBS J,2014,281(16):3656-3666.

      [11] Liu J,Yang J.Uncarboxylated osteocalcin inhibits high glucose-induced ROS production and stimulates osteoblastic differentiation by preventing the activation of PI3K/Akt in MC3T3-E1 cells[J].Int J Mol Med,2016,37(1):173-181.

      [12] Lin G L,Hankenson K D.Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation[J].J Cell Biochem,2011,112(12):3491-3501.

      [13] Park K H ,Kang J W,Lee E M,et al.Melatonin promotes osteoblastic differentiation through the BMP/ERK/Wnt signaling pathways[J].J Pineal Res,2011,51(2):187-194.

      [14] Luchetti F,Canonico B,Bartolini D,et al.Melatonin regulates mesenchymal stem cell differentiation: a review[J].J Pineal Res,2014,56(4):382-397.

      [15] Vriend J,Reiter R J.Melatonin,bone regulation and the ubiquitin-proteasome connection: A review[J].Life Sci,2016,145:152-160.

      [16] Taipaleenm?ki H,Abdallah B M,AlDahmash A,et al.Wnt signalling mediates the cross-talk between bone marrow derived pre-adipocytic and pre-osteoblastic cell populations[J].Exp Cell Res,2011,317(6):745-756.

      [17] Ross S E,Hemati N,Longo K A,et al.Inhibition of adipogenesis by Wnt signaling[J].Science,2000,289(5481):950-953.

      [18] Hu H,Hilton M J,Tu X,et al.Sequential roles of Hedgehog and Wnt signaling in osteoblast development[J].Development,2005,132(1):49-60.

      [19] Gong Y,Slee R B,F(xiàn)ukai N,et al.LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development[J].Cell,2001,107(4):513-523.

      [20] Wang F S,Ko J Y,Yeh D W,et al.Modulation of Dickkopf-1 attenuates glucocorticoid induction of osteoblast apoptosis, adipocytic differentiation, and bone mass loss[J].Endocrinology,2008,149(4):1793-1801.

      [21] Hill T P,Sp?ter D,Taketo M M,et al.Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes[J].Dev Cell,2005,8(5):727-738.

      [22] Beederman M,Lamplot J D,Nan G,et al.BMP signaling in mesenchymal stem cell differentiation and bone formation[J].

      J Biomed Sci Eng,2013,6(8A):32-52.

      [23] Chen G,Deng C,Li YP.TGF-β and BMP signaling in osteoblast differentiation and bone formation[J].Int J Biol Sci,2012,8(2):272-288.

      [24] Lian C,Wu Z,Gao B,et al.Melatonin reversed tumor necrosis factor-alpha-inhibited osteogenesis of human mesenchymal stem cells by stabilizing SMAD1 protein[J].J Pineal Res,2016,61(3):317-327.

      [25] Sun X,Xie Z,Ma Y,et al.TGF-β inhibits osteogenesis by upregulating the expression of ubiquitin ligase SMURF1 via MAPK-ERK signaling[J].J Cell Physiol,2018,233(1):596-606.

      [26] Guo Y C,Wang M Y,Zhang S W,et al.Ubiquitin-specific protease USP34 controls osteogenic differentiation and bone formation by regulating BMP2 signaling[J].EMBO J,2018,37(20)

      [27] Bais M V,Wigner N,Young M,et al.BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells[J].Bone,2009,45(2):254-266.

      [28] Spinella-Jaegle S,Rawadi G,Kawai S,et al.Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation[J].J Cell Sci,2001,114(Pt 11):2085-2094.

      [29] Shimoyama A,Wada M,Ikeda F,et al.Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function[J].Mol Biol Cell,2007,18(7):2411-2418.

      [30] St-Jacques B,Hammerschmidt M,McMahon A P.Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation[J].Genes Dev,1999,13(16):2072-2086.

      [31] Rodda S J,McMahon A P.Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors[J].Development,2006,133(16):3231-3244.

      [32] Tu X,Joeng K S,Long F.Indian hedgehog requires additional effectors besides Runx2 to induce osteoblast differentiation[J].Dev Biol,2012,362(1):76-82.

      [33] Cai J Q,Huang Y Z,Chen X H,et al.Sonic hedgehog enhances the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells[J].Cell Biol Int,2012,36(4):349-355.

      [34] Qin X,Jiang Q,Miyazaki T,et al.Runx2 regulates cranial suture closure by inducing hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in suture mesenchymal cells[J].Hum Mol Genet,2019,28(6):896-911.

      [35] Zanotti S,Smerdel-Ramoya A,Stadmeyer L,et al.Notch inhibits osteoblast differentiation and causes osteopenia[J].Endocrinology,2008,149(8):3890-3899.

      [36] Zamurovic N,Cappellen D,Rohner D,et al.Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity[J].J Biol Chem,2004,279(36):37704-37715.

      [37] Deregowski V,Gazzerro E,Priest L,et al.Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling[J].

      J Biol Chem,2006,281(10):6203-6210.

      [38] Ugarte F,Ryser M,Thieme S,et al.Notch signaling enhances osteogenic differentiation while inhibiting adipogenesis in primary human bone marrow stromal cells[J].Exp Hematol,2009,37(7):867-875.

      [39] Guntur A R,Rosen C J.The skeleton: a multi-functional complex organ: new insights into osteoblasts and their role in bone formation: the central role of PI3Kinase[J].J Endocrinol,2011,211(2):123-130.

      [40] Ghosh-Choudhury N,Abboud S L,Nishimura R,et al.

      Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription[J].J Biol Chem,2002,277(36):33361-33368.

      [41] Fujita T,Azuma Y,F(xiàn)ukuyama R,et al.Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling[J].J Cell Biol,2004,166(1):85-95.

      [42] Lin F H,Chang J B,Brigman B E.Role of mitogen-activated protein kinase in osteoblast differentiation[J].J Orthop Res,2011,29(2):204-210.

      [43] Greenblatt M B,Shim J H,Glimcher L H.Mitogen-activated protein kinase pathways in osteoblasts[J].Annu Rev Cell Dev Biol,2013,29:63-79.

      [44] Son J H,Cho Y C,Sung I Y,et al.Melatonin promotes osteoblast differentiation and mineralization of MC3T3-E1 cells under hypoxic conditions through activation of PKD/p38 pathways[J].J Pineal Res,2014,57(4):385-392.

      [45] McCarthy T L,Centrella M.Novel links among Wnt and TGF-β signaling and Runx2[J].Mol Endocrinol,2010,24(3):587-597.

      [46] Yuasa T,Kataoka H,Kinto N,et al.Sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP-2[J].J Cell Physiol,2002,193(2):225-232.

      (收稿日期:2020-06-03) (本文編輯:張爽)

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