Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (2): 283-288.doi: 10.12307/2022.046
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Fan Danyang1, Fu Runze1, Mi Jiajing1, Liu Chunyan2
Received:
2020-11-12
Revised:
2020-11-14
Accepted:
2020-12-25
Online:
2022-01-18
Published:
2021-10-28
Contact:
Liu Chunyan, MD, Associate chief physician, Associate professor, Department of Orthodontics, School of Stomatology, Hebei Medical University, Hebei Key Laboratory of Stomatology, Hebei Provincial Oral Disease Research Center, Shijiazhuang 050017, Hebei Province, China
About author:
Fan Danyang, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
Supported by:
CLC Number:
Fan Danyang, Fu Runze, Mi Jiajing, Liu Chunyan. Expression and role of cannabinoid receptors during bone remodeling[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(2): 283-288.
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2.1 大麻素受体与骨改建的关系 2.1.1 CB1受体与骨改建的关系 交感神经纤维在骨组织,特别是在骨小梁上密集分布,这些神经纤维与成骨细胞形成突触样结构[15-18]。TAM等[18-19]研究发现,CB1受体在交感神经纤维上存在免疫反应性,在CB1缺失的小鼠中则无此效应,这提示CB1受体存在于支配骨小梁的交感神经纤维中。在交感神经末梢,当突触前膜分泌的去甲肾上腺素激活成骨细胞上的β-2肾上腺素能受体时,成骨细胞的数量和活性就会受到抑制,导致骨形成减少[20]。CB1受体可以与内源性大麻素2-花生四烯酸甘油结合,抑制去甲肾上腺素的释放,这提示骨交感神经末梢的CB1受体可能通过抑制去甲肾上腺素的释放来刺激成骨细胞活性,从而减轻去甲肾上腺素对骨形成的抑制作用[21]。同一研究发现,在创伤性脑损伤模型中,CB1信号能促进外周成骨和骨折愈合,强烈刺激股骨远端部位的骨形成,这主要是由于合成2-花生四烯酸甘油必需的二酰甘油脂肪酶在股骨远端部位表达增强,使2-花生四烯酸甘油水平升高,激活并结合CB1受体,抑制骨交感神经末梢去甲肾上腺素释放和去甲肾上腺素与β2-肾上腺素能受体的结合,从而促进骨形成过程。 另一项研究发现,在C57BL/6J小鼠中,CB1受体的整体缺失会导致骨小梁数量减少[18],表现为低骨量表型,但上述研究结果的获得基于小鼠CB1受体的整体缺失,故其低骨量表型除与骨交感神经末梢CB1受体的单独缺失有关外,还可能与成骨细胞、破骨细胞以及中枢神经元等处的CB1受体缺失相关。在最近的一项研究中,BUSQUETS-GARCIA等[21]利用一种在肾上腺素能/去甲肾上腺素能细胞中缺乏CB1受体的小鼠(DBH-CB1-KO小鼠),研究骨中交感神经末梢CB1受体单独缺失对骨的影响,结果显示这种CB1受体的条件性缺失上调了老年小鼠的骨形成和骨量,表明交感神经CB1受体结构的特异性缺失扰乱了骨组织中的2-花生四烯酸甘油-去甲肾上腺素负反馈回路,并可能通过一种与骨微环境中交感神经纤维去甲肾上腺素释放无关的机制来调节小鼠衰老过程中的骨重建过程。 CB1受体也可通过中枢神经系统调节骨改建过程。CB1受体表达于下丘脑腹内侧核,中枢脂联素可通过下调CB1的表达,增加小鼠骨小梁的数量,脑室注射CB1受体激动剂和拮抗剂能分别减弱和增强中枢脂联素对骨形成的诱导。同时,球状脂联素能增强各种组蛋白去乙酰化酶,尤其是组蛋白去乙酰化酶5的表达水平,从而增强组蛋白去乙酰化酶5与CB1启动子的转录起始位点的结合,这表明可能存在一种中枢APN-HDAC5-CB1信号机制,它能通过对下丘脑CB1表达的表观遗传调控来促进周围骨的形成[22]。 除上述两种途径外,CB1受体还可表达在骨细胞中。在成骨前体细胞,如骨髓间充质干细胞中检测到了CB1 mRNA的表达,同时特异性CB1受体激动剂ACEA对骨髓间充质干细胞表现出显著的归巢反应,而CB2受体选择性激动剂JWH133对骨髓间充质干细胞的归巢则无影响[23]。在人单核细胞、成熟破骨细胞能检测到CB1受体的表达,并且CB1 mRNA的表达在破骨细胞分化过程中保持不变[24]。小鼠成骨细胞和破骨细胞均可表达CB1受体[25-26],但目前的技术并未在人类成骨细胞当中检测到CB1受体的表达[13,27-29]。CB1受体在小鼠中可同时调节成骨细胞和破骨细胞的活性[25,30-31]。具体而言,CB1受体可以通过调节破骨细胞和骨髓间充质干细胞向成骨细胞和脂肪细胞的分化对骨改建产生影响。表达在破骨细胞上的CB1受体在骨改建中发挥着重要的作用。IDRIS等[29]研究发现,人工合成的CB1受体拮抗剂AM251在体外可抑制破骨细胞的形成,AM251在体内可通过抑制破骨细胞性骨吸收来保护卵巢切除所致的骨丢失。与之相反,内源性大麻素激动剂anadamide在体外促进破骨细胞形成,逆转了AM251对于破骨细胞形成的抑制作用。同时,与野生型小鼠相比,CB1基因敲除小鼠产生的破骨细胞能够耐受AM251的抑制作用。SAMIR等[32]展示了抑制CB1受体后幼鼠RANKL基因表达减少和骨保护素表达增加。IDRIS 等[29]的研究提示,CB1基因缺陷小鼠破骨细胞分化缺陷是由于RANKL表达降低,从而削弱了成骨细胞支持破骨细胞分化的能力。以上研究证明CB1受体的激活可以促进破骨细胞形成和骨吸收。 大量研究发现,CB1受体缺失小鼠的骨骼表型不尽相同,这可能与小鼠品系、性别和年龄等因素有关。TAM等[18]研究发现,与野生型小鼠相比,雄性和雌性C57CB1-/-小鼠均表现为低骨量表型;而CD1CB1-/-小鼠骨骼表型则表现出明显的性别差异:雄性CD1CB1-/-小鼠具有明显的高骨量表型,并伴有骨小梁厚度增加;雌性CD1CB1-/-小鼠则表现为骨干轻度异常,皮质骨扩张以及骨干和髓腔直径的增加。IDRIS等[29]研究发现,CD1CB1-/-雌性幼鼠表现出高骨量表型,并可防止卵巢切除引起的骨丢失;同一研究小组发现,CD1CB1-/-小鼠出现了年龄相关性骨丢失增加[32]。这表明CB1受体的激活在小鼠体内会引起幼年动物的骨质丢失,但可以预防晚年与年龄相关的骨质疏松症[26],而年轻的C57BL/6JCB1-/-小鼠中出现了低骨量表型[18],提示在C57遗传背景下的CB1受体似乎发挥着与年龄无关的骨调节作用。SAMIR等[32]通过研究发现,CB1受体拮抗剂Rimonabant能减轻青年大鼠糖皮质激素应用后的骨质疏松症,但却会加重老年大鼠的骨质疏松程度,这些数据表明CB1与骨改建的关系可能与年龄有关[25-26,32]。 CB1受体对机体不同部位的骨改建调节也存在差异。有研究表明,轻微创伤性脑损伤对股骨产生的成骨效应持续时间短暂[19],而对颅骨则相对较长[33]。WASSERMAN等[34]报道了CB1受体在骨骼生长中的作用,CB1受体表达于促进脊椎动物骨骼生长的骨骺生长软骨的肥大软骨细胞中,研究发现,Δ-9-四氢大麻酚对野生型小鼠和CB2-/-小鼠的股骨和腰椎体骨骼生长有抑制作用,但对CB1-/-小鼠则无明显影响,这说明四氢大麻酚对软骨内骨骼生长的抑制是由CB1受体介导的。 综上所述,CB1受体对骨改建的调节可能受多种机制和途径的影响,其具体作用机制仍有待进一步研究。 2.1.2 CB2受体与骨改建的关系 MUNRO等[9]在1993年首次克隆出CB2受体,该受体主要分布在外周的免疫细胞表面。随后有研究在中枢神经系统的不同区域如脊髓、背根神经节和小胶质细胞中检测到了CB2受体的表达[7,35]。与CB1受体相比,CB2受体在成骨细胞、破骨细胞、骨细胞中表达较高。OFEK等[28]的研究报道了CB2 mRNA在小鼠骨髓基质细胞、MC3T3-E1成骨细胞、骨髓来源的破骨细胞及其前体细胞、RAW264.7来源破骨细胞样细胞中的表达,以及CB2受体在野生型小鼠成骨细胞、破骨细胞、骨细胞中的显著表达。此外,CB2受体在人破骨细胞中的表达水平要明显低于单核细胞,并且在破骨细胞分化过程中显著降低[24]。钱红等[36-37]研究发现,人牙周膜细胞也表达CB2受体,且其激活能够促进人牙周膜细胞的成骨分化。 CB2受体主要通过影响成骨细胞分化和活性来影响骨形成。SOPHOCLEOUS等[38]的研究表明,CB2选择性激动剂HU-308可促进野生型小鼠成骨细胞的骨结节形成,但对 CB2-/-小鼠的成骨细胞无效。进一步研究表明,在MC3T3-E1成骨样细胞中,HU-308促进细胞迁移并激活ERK磷酸化,而这些作用可被CB2选择性反向激动剂AM630阻断。在野生型小鼠体内,HU-308可通过刺激骨形成减少卵巢切除引起的骨丢失。与之不同的是,OFEK等[28]的研究显示,这种作用主要归因于骨吸收被抑制。成骨细胞是来源于骨髓间充质干细胞并由RUNX2诱导而来的单核细胞,ZHANG等[39-40]通过研究缺氧条件下CB2受体在骨髓间充质干细胞成骨分化中的作用发现,CoCl2诱导的缺氧使骨钙素、RUNX2等表达水平明显增加,而CB2拮抗剂AM630可部分抑制缺氧诱导的p38和ERK通路,降低RUNX2转录水平,这提示在缺氧条件下,CB2受体参与大鼠骨髓间充质干细胞的成骨分化过程,胡旭治等[41]的研究也得出了相似的结论;CB2受体在恢复骨质疏松症患者骨髓间充质干细胞成骨分化和矿化中也起着重要作用。慢病毒可以诱导CB2受体在骨质疏松患者骨髓间充质干细胞中过表达,CB2过表达能提高碱性磷酸酶的活性,促进成骨基因表达和细胞外基质的矿化沉积,也能增加p38丝裂原活化蛋白激酶的磷酸化,促进骨髓间充质干细胞的成骨分化[42]。有研究发现,CB2的活化能抑制钛粒诱导下MC3T3-E1成骨细胞RANKL的表达,使骨保护素/RANKL比值上升,促进碱性磷酸酶和骨钙素的表达,提高成骨细胞活性,从而促进骨形成[43]。此外,大麻素可能通过CB2介导辅助细胞,间接地刺激骨髓间充质干细胞从骨髓中募集[44]。近来在基因水平的研究发现,miR-187-3p可以通过靶向CB2受体基因的3’非翻译区(UTR)来抑制CB2受体基因的表达,而上调CB2受体基因表达可逆转miR-187-3p对hFOB1.19成骨分化的抑制作用[45]。综上所述,激活CB2受体可以提高成骨细胞活性、促进分化以及相关酶和细胞因子的表达,调节骨形成过程。 CB2受体可以通过调节破骨细胞活性影响骨吸收,但到目前为止,该领域的研究仍存在着争议。OFEK等[28]的研究表明,由于骨转换增加,CB2-/-小鼠会随着年龄的增长而出现骨质疏松的症状,CB2选择性激动剂HU-308既可以抑制骨髓中RANKL诱导的破骨细胞的产生,也可抑制体外RAW264.7培养中RANKL诱导的破骨细胞的形成。另外,ZHU等[46]研究发现,CB2受体激动剂JWH133可以预防类风湿性关节炎局部和全身炎症性骨破坏;ROSSI等[47]利用17-雌二醇对人破骨细胞作用的体外实验发现雌激素可以增加大麻素CB2受体的表达抑制破骨细胞活性。与上述结果相反,TAM等[25]发现,在1-1 000 nmol/L的浓度范围内,花生四烯乙醇胺、2-花生四烯酸甘油、HU-308以及JWH133可促进巨噬细胞集落刺激因子和RANKL诱导的破骨细胞形成,CB2反向激动剂AM630则对破骨细胞的形成具有抑制作 用[25,48]。进一步研究表明,与野生型小鼠相比,从CB2缺陷小鼠中分离的骨髓细胞对RANKL的反应较弱,产生的破骨细胞较少,可减少卵巢切除引起的骨丢失的影响。SCHUEHLY等[49]发现一种新的具有高度选择性的CB2配体,在体外培养过程中,这种配体可以强烈抑制RANKL诱导的小鼠和人类破骨细胞生成,同时证明内源性大麻素可以刺激破骨细胞的形成。在体内,CB2受体拮抗剂可以抑制成年小鼠破骨细胞的形成,减少骨丢失。IDRIS等[48]还发现,AM630可以预防卵巢切除引起的骨丢失,并且这一反应依赖于给药剂量。此外,LUNN等[50]报告称新型CB2选择性拮抗剂Sch.036可以预防关节炎小鼠的骨损伤。 ROSS[51]报道了CB2选择性拮抗剂AM630在高浓度 (10 μmol/L)时刺激人破骨细胞形成,这与IDRIS等[48]报道的AM630对小鼠培养的破骨细胞形成的抑制作用完全相反。其原因尚不清楚,可能与AM630作用的物种差异性、所使用的高浓度AM630的非靶点效应、以及不同的血清选择等因素有关[52]。 除此之外,CB2受体缺失小鼠的骨骼表型不尽相同,这可能与小鼠品系、年龄和性别等因素有关。SOPHOCLEOUS等[53]将Cnr2-/-CD1小鼠与Cnr2-/-C57BL/6小鼠进行了比较,研究发现,Cnr2-/-C57BL/6小鼠的骨小梁量与野生型相似,而年轻雌性Cnr2-/-CD1小鼠较野生型小鼠具有较低的骨转换率和较高的骨小梁量。在雄性小鼠中,Cnr2-/-和野生型的骨骼表型没有显著差异,但两种性别的Cnr2-/-和野生型小鼠的皮质骨表型相似。随着年龄的增长,C57BL/6Cnr2-/-小鼠和Cnr2-/-CD1小鼠较野生型小鼠骨量减少,而在12个月时,Cnr2-/-CD1小鼠和野生型小鼠之间的松质骨体积却没有差异。 2.1.3 GPR55受体与骨改建的关系 许多实验发现CB1和CB2基因敲除动物中仍然保留着大麻素类效应,这提示体内存在着除上述两种受体以外的大麻素受体。目前已经确定了的其他大麻素受体包括GPR55和瞬时受体电位阳离子通道1 [54-55]。 GPR55受体基因定位于人类2q37号染色体上,其首次发现于中枢神经系统[56],随着研究的不断深入,GPR55也被证明在骨代谢中发挥相关作用[57]。WHYTE等[57]发现在依赖巨噬细胞集落刺激因子单核细胞来源的人破骨细胞、人和小鼠多核破骨细胞和原代成骨细胞以及人TE85成骨样细胞中均能检测到GPR55 mRNA的表达,GPR55 mRNA在人破骨细胞中的表达高于人破骨前体细胞。进一步研究发现,GPR55受体激动剂O-1602对体外培养小鼠破骨细胞的形成有抑制作用,而对人破骨细胞的形成无影响;GPR55受体拮抗剂CBD却能显著促进人破骨细胞的形成[57]。OSSOLA等[58]研究证实CBD能以时间和浓度依赖的方式促进脂肪来源间充质干细胞的募集,而GPR55受体激动剂O-1602可抑制CBD诱导的募集,阻碍间充质干细胞的成骨分化,这提示GPR55受体可能在成骨细胞分化和破骨细胞形成过程中发挥着不同的作用。 2.1.4 瞬时受体电位阳离子通道1受体与骨改建的关系 研究发现瞬时受体电位阳离子通道1在来源于人外周血单核细胞的破骨细胞中表达,并且通过提高花生四烯乙醇胺水平,可以引起瞬时受体电位阳离子通道1介导的对破骨细胞形成的刺激作用[59]。此外,瞬时受体电位阳离子通道1也存在于人骨髓间充质干细胞上,与CB2受体在体外对人成骨细胞活性的促进作用相反,瞬时受体电位阳离子通道1受体激活后会抑制成骨细胞活性,阻碍骨形成。 CB1、CB2、GPR55以及瞬时受体电位阳离子通道1受体均属于7次跨膜蛋白,在体内外可以与不同配体结合参与骨改建过程。大麻素受体与其配体的亲和力与其种类密切相关,不同配受体间的结合以及受体间的联合作用可对成骨细胞、破骨细胞和骨髓间充质干细胞的分化和活性产生不同的生物学效应,见图2。成骨、破骨细胞将这种复杂的效应转换成对骨形成和骨吸收过程的精密调节,使大麻素系统在骨改建的动态平衡中起到了重要的调控作用,为临床骨相关疾病的治疗和研究提供了新的思路。 2.2 大麻素受体与骨质疏松 骨质疏松症是一种因骨骼强度丧失导致脆性骨折的疾病,其主要特征为骨形成缺陷和骨吸收过多,使得骨量丢失和骨骼结构破坏。骨质疏松症的常见病因为缺乏雌激素和应用糖皮质激素治疗,这两者都与骨吸收增强和骨形成减少有关[60]。 雌激素缺乏会使妇女绝经后立即进入加速的骨丢失阶段,从而导致骨吸收和骨形成的失衡[61]。近些年大麻素受体被认为对雌激素缺乏性骨质疏松症有调节作用。研究发现CB1选择性拮抗剂AM251和CB2选择性拮抗剂AM630能减少体内破骨细胞的生成,从而减轻成年小鼠卵巢切除引起的骨丢失[25-26,48]。此外,CB1-/-小鼠能免受卵巢切除引起的骨丢失的影响,CB2受体缺陷小鼠的骨丢失仅比野生型小鼠略有减少[41,48]。最近研究证实CB2受体基因的多态性与绝经后妇女骨质疏松症具有相关性[62],这表明CB2受体基因在未来可能成为治疗骨质疏松症的靶点。 糖皮质激素诱导的骨质疏松症是最常见的继发性骨质疏松症。临床研究发现,慢性糖皮质激素治疗与低骨密度和高骨折易感性密切相关[63-67]。应用糖皮质激素会使大鼠患上骨质疏松症,而应用CB1拮抗剂AM251后,骨质疏松大鼠成骨细胞凋亡减少、活性增强,减轻了糖皮质激素对骨形成的负面影响[68-69]。但有研究发现,CB1受体拮抗剂利莫那班(Rimonabant)虽然能减轻年轻大鼠糖皮质激素应用后的骨质疏松症,但会加重老年大鼠的骨质疏松程度,这提示临床应用的拮抗剂药物可能具有年龄相关性。BELLINI等[70]发现激活CB2受体可以抑制甲基强的松龙引起的破骨细胞过度活化,这提示CB2受体在防治糖皮质激素诱导的骨量丢失方面有一定的应用价值。 2.3 大麻素受体与牙周炎 牙周炎是一种由细菌等多种因素引起的慢性炎症破坏性疾病,与炎症免疫和骨代谢密切相 关[63-64,71]。牙周炎病变过程中局部组织产生多种炎症递质以及细菌及其毒素进入血液,可能会增加很多系统性疾病的风险[72]。最近有研究证实大麻素受体在牙周组织骨代谢和炎症愈合等方面发挥着重要作用。YAN等[73]发现炎症环境下CB1受体激活能通过p38丝裂原活化蛋白激酶和JNK信号通路增强牙周膜干细胞的成骨/牙本质分化能力,从而为成骨分化营造良好的微环境。同时有研究发现,CB2受体的激活可以调节脂多糖诱导的人牙周韧带细胞促炎因子的产生和破骨细胞基因的表达[36]。激活CB2受体对脂多糖刺激的人牙周膜细胞具有抗炎和抗吸收作用,这提示大麻素受体活化可能是治疗牙周炎症、减缓牙槽骨吸收的有效策略。 "
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