Chinese Journal of Tissue Engineering Research ›› 2013, Vol. 17 ›› Issue (2): 347-352.doi: 10.3969/j.issn.2095-4344.2013.02.029
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Wang Dan, Bao Jie, Wang Guo-xiang
Received:
2012-04-01
Revised:
2012-05-16
Online:
2013-01-08
Published:
2013-01-08
Contact:
Wang Guo-xiang, Doctor, Professor, Doctoral supervisor, Sport and Physical Education School of Soochow University, Suzhou 215021, Jiangsu Province, China kwang63@163.com
About author:
Wang Dan★, Studying for master’s degree, Sport and Physical Education School of Soochow University, Suzhou 215021, Jiangsu Province, China wangdan6953@126.com
Supported by:
Supported by: the General Program of the Natural Science Foundation of Universities in Jiangsu Province, No. 11KJD320001
CLC Number:
Wang Dan, Bao Jie, Wang Guo-xiang. Parathyroid hormone regulation for related protein and receptor activator of nuclear factor-kappa B in bone metabolism[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(2): 347-352.
2.1 甲状旁腺激素在骨代谢中的作用 骨重建的一个关键调控因素是甲状旁腺激素,骨髓基质干细胞、前成骨细胞和成骨细胞均是骨组织中应答甲状旁腺激素信号的主要细胞[1]。甲状旁腺激素激活破骨细胞的功能是间接通过作用于成骨细胞而发挥其对骨吸收的调控作用。在成骨细胞或者干细胞中,甲状旁腺激素是影响RANKL表达的最有潜力的影响激素[2-3]。在松质骨中,甲状旁腺激素调控骨重建的一个显著特征是成骨细胞募集的数量是充分填充被破骨细胞吸收之后形成空腔的关键。而这又是激素刺激物作用于RANKL合成实现的[4]。 甲状旁腺激素的受体有两种即Ⅰ型和Ⅱ型,甲状旁腺激素Ⅰ受体主要分布于骨骼及肾脏组织,为经典的 甲状旁腺激素受体。1993 年由Brown等从牛甲状旁腺中克隆出[5]。甲状旁腺细胞表面的细胞外钙敏感受体将细胞外钙浓度的变化转换为信号传导入细胞内,引起一系列生理变化。骨骼系统是细胞外钙敏感受体分布最多的地方,成骨细胞、破骨细胞均有细胞外钙敏感受体表达。甲状旁腺激素受体为GPCR (G-protein-coupled receptor,GPCR) 超家族中B亚族成员,该受体有7个跨膜区[6]。 甲状旁腺激素通过其受体激活成骨细胞内2种信号传导通路:一种是蛋白激酶A信号通路(protein kinase A pathway,PKA),另一种是蛋白激酶C信号通路(protein kinase C pathway, PKC)[7]。甲状旁腺激素主要通过PKA信号通路,调节其下游反应蛋白,cAMP-PKA信号通路被认为是甲状旁腺激素信号的传导主要通道[8-9]。 甲状旁腺激素对成骨细胞蛋白质合成及相关基因表达有着重要的调控作用,在体内或体外实验、不同来源的成骨细胞、不同分化周期的成骨细胞或甲状旁腺激素应用时间不同等情况下,甲状旁腺激素起的作用不同。甲状旁腺激素与其受体结合,激活PKA和PKC两条信号传导通道。通过这两条通道调控核结合因子等转录因子。甲状旁腺激素通过PKA通路刺激基质金属蛋白酶3启动子而使核结合因子磷酸化,并通过cAMP反应元件结合蛋白(CREB)的磷酸化上调转录激活蛋白。基质金属蛋白酶3基因启动子上2个保守的加强序列,任何一个位点发生突变,都可阻碍核结合因子或转录激活蛋白1的结合,从而抑制甲状旁腺激素对转录启动的激活作用。核结合因子及转录激活蛋白1同时表达过高能增强甲状旁腺激素的应答反应[10]。核结合因子对成骨细胞分化起着关键的调控作用,在整个发育过程中,其合成与骨形成密切相关。 2.2 甲状旁腺激素对骨保护素/RAKNL调整作用的相关研究 RANKL是目前发现惟一具有诱导破骨细胞分化、发育、发挥功能的因子,RANKL不仅促进破骨细胞分化,而且呈剂量依赖性地激活成熟破骨细胞、延长其存活时间和形成骨吸收陷窝的能力[11-12]。RANKL是调节骨吸收的关键因子,通过与RANK结合发挥功能。RANK介导的信号是破骨细胞分化、活化的一道关键闸门。RANKL与RANK结合后,启动RANKL信号转导,骨保护素则与RANKL竞争性结合RANK,RANKL/骨保护素比值决定破骨细胞分化、成熟及功能[13]。 20世纪30年代第1次观察到甲状旁腺激素对骨合成代谢有影响的特性[14]。直到50年后,Tam才分别出间歇和持续给予甲状旁腺激素对骨代谢有不同作用[15]。Jilka等[16]给6月龄老年大鼠分别注射5 d的甲状旁腺激素(470 ng/h)和RANKL (525 ng/h)。甲状旁腺激素和RANKL都能增加成骨细胞和破骨细胞的数量,但是注射甲状旁腺激素组的成骨细胞与破骨细胞的比值和骨形成明显高于注射RANKL组。大鼠的松质骨内含有大量甲状旁腺激素而有少量RANKL,提示维持骨重建平衡除了破骨细胞作用之外,还需要成骨细胞相关基因表达的作用。与这个观点一致的是,甲状旁腺激素降低了Wnt抑制剂的水平并且增加了Wnt目标因子NKd2,Wisp1和Twist1表达。在骨骼中,Wnt信号刺激骨保护素表达,并且抑制骨吸收是大家公认的[17]。越来越多研究证明了在成骨细胞中,同样的信号通路也是RANKL的重要的调控者。在体外实验中,Wnt信号通路/β-连环蛋白受到刺激后,会抑制RANKL表达,相反,剔除β-连环蛋白会增加RANKL表达[18]。持续的甲状旁腺激素增加了RANKL的表达,因此增加了新的破骨细胞的生成。但是,这些成骨细胞的数量和质量不能够完成填充骨空腔。只有通过甲状旁腺激素刺激WNT信号通路来完成[19]。 Yusuke在研究甲状旁腺激素对骨合成代谢影响机制中证明了,持续和间歇性甲状旁腺激素的直接作用是成骨细胞分化[20]。随着甲状旁腺激素增加甲状旁腺激素rP表达和cAMP积累与成骨细胞分化是一致的。持续甲状旁腺激素刺激成骨细胞表达RANKL,促使骨髓细胞中破骨细胞产生,通过细胞间的作用导致骨吸收;而间歇性甲状旁腺激素刺激成骨细胞分泌胰岛素样生长因子1,进而刺激成骨前体细胞分泌IRS-1,通过旁分泌机制导致骨吸收。 Jacome-Galarza[21]曾经提到甲状旁腺激素不但增加成骨细胞的数量,也可以增加早期造血干细胞的数量。成骨细胞发挥其做的关键就是RANKL。他对8周大鼠分别进行7 d和14 d的甲状旁腺激素注射,发现注射7 d甲状旁腺激素组的大鼠的骨髓中造血干细胞有显著的增加,而注射14 d组的造血干细胞的数量是7 d的39%,同时,对成骨前体细胞的分化没有任何的影响。两组的RANKL都有所增加,但是前者的增加幅度比后者大。 Huang等[22]体外培养细胞28 d,期间分为4个时间段来接触甲状旁腺激素 2 h(7,14,21,28 d)。甲状旁腺激素在不同的时期调控骨保护素mRAN、RANKL mRAN的表达。在初级骨髓细胞中破骨细胞分化的晚期,甲状旁腺激素显著的提高了RANKL mRAN的表达;在破骨细胞整个分化期,甲状旁腺激素抑制了骨保护素mRAN表达。实际上甲状旁腺激素在不同时期对RANKL、骨保护素有不同作用,从而形成调控成骨细胞形成的新模式。因此,甲状旁腺激素在调控骨代谢机制中有一个转换,骨保护素在破骨细胞分化的早期起主导作用,RANKL在破骨细胞分化的晚期期间对成骨细胞的调控起着关键作用。 已有研究表明,甲状旁腺激素通过PKC通道刺激破骨细胞抑制性凝集素来提高RANKL表达[23]。相反,这些促骨因子抑制了骨保护素表达。在大鼠颅骨的初级破骨细胞的试验中,当甲状旁腺激素刺激破骨细胞抑制性凝集素水平达到最高时,RANKL被引诱表达,而骨保护素受到抑制。Scott等[24]的人体试验中,20人分别进行8 d适当训练和剧烈、疲劳性训练。两组骨保护素在训练后都比训练前有所增加,但是后者骨保护素有着显著性增加,同时甲状旁腺激素也比训练前显著增加。两者训练4 d,骨吸收增加,而不是骨形成增加。提示骨吸收的增加有可能与甲状旁腺激素增加有关。 目前研究发现,不同甲状旁腺激素给药方式对于RANKL/骨保护素比率的调节作用是不同的,从而表现对骨吸收调控作用的不同。Locklin等[25]人的研究表明了:持续甲状旁腺激素有利于破骨细胞的连续的分化,募集和活化。相反,如果甲状旁腺激素间歇性的注射,很少见到骨吸收。除此之外,人工培养大鼠骨髓细胞的实验提供了更深层次的依据,给大鼠骨髓细胞持续的甲状旁腺激素长生了大量的多核的破骨细胞,并且使RANKL:骨保护素的比值增加了25倍,间歇性的甲状旁腺激素增加了成骨细胞分化的标志物,但是RANKL:骨保护素的比值没有发生变 化[26]。在长期给大鼠注射甲状旁腺激素的试验中, 24 h内观察骨保护素mRAN呈持续下降的趋势,而RANKL mRAN持续增加。抑制骨保护素的产生加强了甲状旁腺激素对破骨前体细胞基因的表达。 Galli等[27]的研究中,在成年大鼠中剔除甲状旁腺激素的受体之后,提高了RANKL基因的转录,减少了这种细胞因子的表达,降低了骨重建的速率。实验充分证明甲状旁腺激素通过刺激RANKL的合成来调控骨重建的重要性。这些实验数据充分的说明了RANKL:骨保护素是骨吸收的基础,受甲状旁腺激素的调节。甲状旁腺激素是通过成骨细胞直接引起骨吸收的[28],是成骨细胞分泌的配体RANKL与破骨前体细胞分泌的配体RANK之间的相互作用,RANK是破骨细胞募集,分化和活化的重要影响因素,骨保护素可以抑制RANKL和RANK之间的相互作用,因此,RANKL:骨保护素的比例将会影响破骨细胞的分化和活跃的程度。 此外,在临床方面间歇性的给予甲状旁腺激素已经作为了牙组织修复的一种治疗方法[29]。最近的临床研究表明,骨保护素、RANKL在由牙周炎引起牙槽骨丢失中起着关键作用。在有关牙周膜不同领域研究中发现提高RANKL或降低骨保护素表达会导致牙槽骨的丢失。PDL细胞表达甲状旁腺激素的受体[30],PDL细胞间歇性的注射甲状旁腺激素,伴随骨保护素/RANKL比值增加,破骨细胞形成也不断增加。在成熟PDL细胞和RAW264.7细胞共培养实验中间歇注射甲状旁腺激素发现,破骨细胞活化增加,骨吸收增加,同时伴随骨保护素/RANKL的比值下降。间歇性甲状旁腺激素影响PDL细胞中骨保护素/RANKL比值。提示激素调控PDL细胞微环境潜在机制和牙周膜修复过程中的合成作用。 在骨折的治疗方面也有研究,已有一些技术应用到骨骼修复中,但这些技术中需要手术干预,在随后恢复过程中可能会引发并发症。最近大多数研究已经证实系统性给予甲状旁腺激素可以作为提高骨折修复的另一个方法。Komrakova [31]在甲状旁腺激素对健康大鼠骨折和切除卵巢大鼠骨折修复研究中表明,给予甲状旁腺激素7d后,增加了所有大鼠的骨骼系数,在健康大鼠组效果更佳。提示在治疗早期甲状旁腺激素可能通过调控RANKL /骨保护素比值来提高骨形成。"
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