Activation of cannabinoid receptors promotes periodontal healing by regulating periodontal inflammation and bone remodeling

doi:10.12307/2023.530

Abstract

Abstract: BACKGROUND: Cannabinoid receptors, by binding to ligands, modulate inflammation and bone volume in periodontitis and promote healing of periodontal tissue, which is of great significance in the clinical prevention and treatment of periodontitis.
OBJECTIVE: To review the relation between cannabinoid receptors and periodontitis, mainly cannabinoid type I (CB1) receptor and cannabinoid type II (CB2) receptor in relation to inflammation and remodeling of the alveolar bone, and the common cellular signaling pathways involved, thereby providing ideas for the prevention and treatment of periodontitis and its application in other clinical areas.
METHODS: Relevant literature included in PubMed, WanFang database, and CNKI Database from July 1985 to July 2022 was searched. Search terms were “cannabinoids receptor, CB1 receptor and periodontitis, CB2 receptor and periodontitis, CB1 receptors and bone remodeling, CB2 receptors and bone remodeling, CB1 receptors and signaling pathways, CB2 receptors and signaling pathways” in English and Chinese. Totally 107 papers were finally included for review.
RESULTS AND CONCLUSION: The endogenous cannabinoid system contains multiple receptors, the most representatives of which are CB1 and CB2 receptors, two members of the G protein-coupled superfamily. Both CB1 and CB2 receptors are expressed in periodontal tissue. In the presence of natural ligands or synthetic agonists, cannabinoid receptors can produce specific physiological effects in vitro and in vivo through different metabolic pathways. Then they can regulate the local inflammation and osteocyte generation and differentiation in periodontitis, ultimately influencing inflammation and bone mass. Further studies are needed on the relation between cannabinoid receptors and periodontitis inflammation and alveolar bone formation and resorption, as well as the common signaling pathways involved, such as mitogen-activated protein kinase signaling pathway and nuclear factor-κB signaling pathway. It has become the focus of current research to provide new ideas for the prevention and treatment of periodontitis in clinical practice.

Key words: cannabinoid, CB1 receptor, CB2 receptor, periodontitis, inflammation, bone remodeling, MAPK signaling pathway, NF-κB signaling pathway

CLC Number:

Zhao Yuan, Zhai Haoyan, Liu Chunyan. Activation of cannabinoid receptors promotes periodontal healing by regulating periodontal inflammation and bone remodeling[J]. Chinese Journal of Tissue Engineering Research, 2023, 27(26): 4214-4222.

Figures/Tables 4

2.1 CB1受体和牙周炎的关系 2.1.1 CB1受体和牙周组织炎症的关系 CB1受体与配体结合后，可通过下调牙周组织中的炎症递质水平调控牙周炎。有研究表明，CB1受体在发炎组织的愈合中具有调节作用[40]。 KONERMANN等[41]研究表明，CB1受体与配体结合后可导致牙周组织的炎症减少。CP55940是CB1受体的激动剂，它通过激活CB1受体促进人牙龈成纤维细胞的伤口愈合[42]。虽然CB1受体在牙周组织中表达较少，但可以通过介导抗炎相关细胞途径参与对炎症反应的保护作用[37]。OSSOLA等[38]应用CB1受体选择性激动剂甲酰胺于大鼠牙周炎实验模型中，发现甲酰胺可减少牙槽骨丢失和炎症参数。AEA可以减少牙周炎牙龈组织中肿瘤坏死因子α的产生，使用CB1受体拮抗剂AM251可以减弱AEA的作用[43]。AEA剂量依赖性地减少脂多糖诱导的人牙龈成纤维细胞中白细胞介素6、白细胞介素8和单核细胞趋化蛋白1(MCP-1)的产生。此外，通过预处理大麻素CB1和CB2受体的有效和选择性拮抗剂，即AM251和SR144528，AEA的作用减弱，表明大麻素受体参与介导AEA诱导的人牙龈成纤维细胞抗炎作用[37]。过氧化物酶体增殖物激活受体(peroxisome proliferator-activated Receptors，PPAR)是核激素受体家族中的配体激活受体[44]。在炎症反应中，PPAR-γ抑制炎症信号通路和炎症递质的产生[45]。PPAR-γ的激活，通常与CB1受体的激活相结合，可以介导大麻素的抗炎，镇痛，代谢，神经保护，抗肿瘤和心血管作用[46]。 CB1受体在牙周组织中表达较少，但可以通过介导一些细胞途径激活机体的一系列抗炎反应，减少牙周组织中炎症递质的产生，进而减少牙槽骨吸收。但是由于分布在牙周组织中的主要为CB2受体，所以在牙周炎的发生发展过程中CB2受体发挥主要的炎症调控作用。 2.1.2 CB1受体和牙槽骨骨改建的关系 CB1受体参与骨组织中的骨骼调节和骨代谢。据报道，在大鼠牙周炎模型中，使用CB1受体特异性激动剂AEA类似物治疗可显著减轻牙槽骨的丢失[38]。OSSOLA等[38]应用CB1受体选择性激动剂甲酰胺于大鼠牙周炎实验模型中，发现甲酰胺可减少牙槽骨丢失和炎症参数。 CB1受体主要通过影响成骨细胞的分化调控牙槽骨骨改建。YAN等[47]研究了CB1受体拮抗剂AM251在炎症环境中抑制牙周膜干细胞(PDLSCs)中的成牙/成骨分化能力。CB1受体在小鼠骨髓间充质干细胞的成骨分化过程中被激活，CB1受体增强骨髓间充质干细胞的早期成骨能力并影响其在急性应激期间的存活率[48-49]。一项研究报道，CB1受体调节小鼠的骨髓间充质干细胞迁移/归巢，且骨髓间充质干细胞功能可以通过CB1受体特异性激动剂ACEA增强，并被CB1特异性拮抗剂AM281削弱[50]。PPAR可以调节骨髓间充质干细胞向成骨细胞分化，由于PPAR-γ的激活通常与CB1受体的激活相结合，所以CB1受体一定程度上也可以促进成骨细胞的形成[51]。 CB1受体可以促进炎症状态下牙周膜细胞的成骨能力，促进成骨细胞的形成，减少骨丢失。但是，CB1受体在牙周组织中少有分布，牙周组织中成骨细胞、破骨细胞、骨细胞分布的主要为CB2受体，所以CB2受体在牙周炎骨改建中似乎发挥更为明显的作用。CB1受体与牙周炎的关系见图3，CB1受体炎症环境下参与牙周组织再生的机制仍有待进一步研究。"

2.2 CB2受体和牙周炎的关系大麻素可有效抑制体外白细胞和急性炎症动物模型中的免疫和炎症功能，例如肺、心肌、血管、牙周、神经、肝脏、胰腺和关节炎炎症模型，其中非精神活性大麻素受体CB2受体正在成为大麻素调节炎症的关键靶标[52]。CB2受体可能在骨代谢和炎症中发挥重要作用[53]。牙周炎中关于CB1和CB2基因表达的研究显示，CB2受体在牙龈组织中显著表达，而CB1受体无明显表达[13]。因此，大多数关于炎症性疾病中大麻素受体的研究仅限于CB2受体及其激动剂，CB2受体可能与牙周炎的关系更为密切。 2.2.1 CB2受体牙周组织炎症的关系 CB2受体在抗炎途径激活和免疫抑制作用方面发挥重要作用[54]。CB2受体激动剂HU-308和反向激动剂SMM-189在原代人牙周膜成纤维细胞(human periodontal ligament Fibroblasts，HPDLF)中表现出抗炎活性[55]。另有研究表明， CB2受体反向激动剂SMM-189可以显著抑制促炎细胞因子干扰素γ、白细胞介素6和白细胞介素12 p70(IL-12p70)的产生[56-57]。AEA可以减少牙周炎牙龈组织中肿瘤坏死因子α的产生，使用CB2受体拮抗剂AM630可以减弱AEA的作用[43]。有研究报道，牙周术后患者的炎症牙龈成纤维细胞中CB2受体的表达升高，这与龈沟液(gingival crevicular fluid，GCF)中的AEA和2-AG的上调有关[40]，这表明牙周手术后内源性大麻素的增加可能促进牙龈成纤维细胞的增殖，有利于炎症愈合。 CB2受体与配体结合，可降低牙周组织的促炎细胞因子水平，发挥显著的抗炎作用。ABIDI等[59]研究发现CB2受体配体抑制促炎细胞因子/趋化因子的产生，并通过减少牙周组织破坏和牙槽骨吸收来减轻炎症，其中选择性CB2受体反向激动剂SMM-189对细胞因子、趋化因子和血管标记物的抑制程度大于激动剂HU-308，表明CB2受体反向激动剂可以作为治疗牙周炎症的新方法。ABIDI等[29]首次研究证明CB2受体反向激动剂是开发牙周炎新治疗干预的可行候选者。研究结果显示，与AEA和HU-308相比，SMM-189在抑制白细胞介素6和单核细胞趋化蛋白1(MCP-1，与慢性牙周炎相关的促炎标志物)表达方面的活性显示出更好的抗炎作用或免疫抑制作用。在用牙龈卟啉单胞菌脂多糖所诱导形成的炎症中，人牙周膜成纤维细胞中白细胞介素1、肿瘤坏死因子α、白细胞介素6和单核细胞趋化蛋白1的产生被CB2受体激动剂和反向激动剂抑制[55]。OSSOLA等[60]在患有牙周病的大鼠中使用了CB2受体激动剂HU-308，结果表明牙周组织中炎症递质的量减少，证明CB2信号参与了牙周损伤的控制。一些研究表明，电针治疗通过激活CB2受体降低牙周促炎递质的表达[61-62]。研究表明CB2受体可以显著降低牙周组织中促炎因子的水平从而发挥其抗炎作用，用CB2受体配体治疗牙周炎在很大程度上尚未探索，并且仍有待确定哪一类配体，即激动剂或反向激动剂，在牙周炎中产生最佳的抗炎活性[63]。 2.2.2 CB2受体和牙周炎牙槽骨骨改建的关系 CB2受体激活与成骨分化和矿化增加相关，它将刺激成骨细胞分化，并减轻破骨细胞的生成，这表明CB2受体信号通过直接作用于骨细胞，同时通过抑制促吸收细胞因子的表达来阻断骨丢失[64-65]。有研究表明，在成骨细胞、骨细胞和破骨细胞中有CB2受体的表达，而CB1受体的表达非常低或未观察到[66]。CB2受体在维持骨量方面发挥重要作用，一方面是刺激基质细胞/成骨细胞，此外是通过抑制破骨细胞，降低核因子κB受体活化因子配体(receptor activator of nuclear factor-κB ligand，RANKL)的可用性。RANKL是一种关键的破骨细胞生成因子[67-68]，对破骨细胞前体细胞的完全分化至关重要，在牙周骨吸收中起关键作用[69]。至于CB1受体，已经证明中枢CB1受体刺激可能导致由肾上腺素能系统调节的外周骨形成[70]。一直以来，已经证明CB2受体在成骨过程中发挥重要作用。体外研究表明，CB2受体刺激通过增加Runx2、骨涎蛋白、骨保护素(OPG)、碱性磷酸酶和骨钙素等成骨因子对成骨细胞增殖和功能产生积极影响[64]。根据研究，Schmuhl等[71]报道，CB2受体拮抗剂AM630抑制大麻二酚诱导的脂肪来源的间充质干细胞迁移和成骨细胞分化。QIAN等[72]证明，CB2受体的激活能够增强牙周膜细胞的成骨分化，HU-308上调成骨相关蛋白(OPG)基因表达，而下调RANKL基因，导致OPG/RANKL比值升高，并且HU-308使牙周膜细胞矿化加速。 CB2受体可以抑制破骨细胞的功能，减少牙槽骨骨丢失。牙周炎大鼠施加大麻二酚刺激后的牙槽骨丢失减少，RANKL/RANK的激活剂表达降低[73]。OSSOLA等[60]的研究结果表明HU-308可以明显减少牙槽骨丢失和牙龈组织中的炎症递质，在没有治疗的情况下，脂多糖诱导的牙周炎会增加牙槽骨丢失；使用HU-308治疗后，牙龈炎症参数的衰减导致骨代谢正常化。由于牙周组织中CB2受体分布明显多于CB1受体，上述多项研究说明CB2受体及其激动剂可以有效减少牙周炎过程中牙槽骨的丢失，所以牙周炎时CB2受体与配体结合后，可以刺激成骨细胞分化，促进成骨细胞的形成，抑制破骨细胞的骨吸收，进而减少炎症过程中牙槽骨丢失。CB2受体与牙周炎关系见图4。"

MAPK信号通路在人类脂肪来源的干细胞成骨中是必需的[85]。CB1受体主要是通过激活p38 MAPK和JNK信号通路，抑制了Erk1/2信号通路影响牙周膜干细胞和骨髓间充质干细胞的功能和分化，从而调控牙周炎的炎症水平和骨量。YAN等[47]研究发现，CB1受体激活了P38 MAPK和JNK信号，抑制了牙周膜干细胞中的Erk1/2和PPAR-γ信号，并可激活肿瘤坏死因子α和干扰素γ刺激抑制的p38 MAPK和JNK信号，PPAR-γ表达增加，但炎症条件下磷酸化的Erk1/2水平没有变化，炎症条件下该过程可能独立于Erk1/2。所以CB1受体可激活牙周膜干细胞的成骨/牙本质分化潜力并上调了肿瘤坏死因子α或干扰素γ刺激的牙周膜干细胞的成骨/牙本质分化潜力。所以，CB1受体通过p38 MAPK和JNK信号通路挽救受损牙周膜干细胞的功能，而不是通过Erk1/2信号通路。p38 MAPK和JNK是成骨分化的积极调节因子[86-87]。PPAR-γ是成骨分化的负调节因子，PPAR-γ的抑制导致成骨增强[88-89]。YAN等[90]进一步在CB1受体对于间充质干细胞功能的机制方面进行研究，发现CB1受体激活了骨髓间充质干细胞中的p38 MAPK和JNK信号通路并抑制了Erk1/2信号通路，证明CB1受体在间充质干细胞功能调控和牙周组织再生中的潜在作用，为炎症条件下的骨组织再生提供了新的作用靶点。所以CB1受体可以通过不同的机制挽救牙周膜干细胞的增殖和成骨/成牙分化能力，p38 MAPK和JNK信号通路似乎对于炎症抑制时的CB1受体激活的牙周膜干细胞的增殖和成骨/牙分化潜力更为重要。 CB2受体主要是通过激活ERK1/2、抑制p38信号通路，增加牙周成骨相关基因的表达，同时影响牙周组织中细胞的功能，调控牙周组织的炎症。据报道，大麻素通过激活p-ERK、p-p38和Akt积极调节牙龈成纤维细胞[40]，而在单核细胞中也可以看到细胞特异性差异，例如p-ERK和Akt被激活，而不是p-p38[91]。在体外模型中，CB2受体激动剂抑制cAMP的产生，这已被证明会导致ERK的磷酸化[91-93]。选择性CB2受体拮抗剂AM630抑制大麻二酚诱导的MAPK信号通路，大麻二酚通过炎症微环境中的p38-MAPK信号通路促进骨髓间充质干细胞的成骨分化[94]。所以，大麻二酚通过结合CB2受体干预p38 MAPK，并增加了炎症环境中成骨相关mRNA和蛋白的表达水平。大麻素可以通过CB2依赖的方式促进牙周膜成纤维细胞的黏附和迁移，这些是通过涉及ERK1/2激活和p38抑制的MAPK信号级联的FAK激活介导的[5]。特异性阻断CB2受体可消除大麻素对这些细胞活性的影响。研究表明Δ-9-四氢大麻酚(THC，一种可以从植物中提取的大麻素)通过结合CB1/CB2受体增加FAK磷酸化，并启动MAPK下游信号转导通路，激活ERK1/2，抑制p38信号通路，促进牙周组织中细胞的黏附和迁移[5]。CB2受体拮抗剂AM630特异性阻断CB2后，细胞信号传导显著减弱。CB1受体拮抗剂AM251选择性阻断CB1后，FAK磷酸化很少被抑制，所以CB2受体在激活MAPK信号通路方面起决定性作用。当CB1和CB2受体同时被阻断后，THC几乎不能传导细胞信号，二者表现为协同作用。白细胞介素1β刺激的人牙周膜成纤维细胞对p-JNK没有任何影响，而仅用CB2受体配体SMM-189(反向激动剂)治疗显著上调p-JNK活性。SMM-189对p-JNK的这种独特作用可能负责控制在创伤愈合(组织修复和细胞迁移)以及胶原蛋白生物合成和基质收缩中必不可少的成纤维细胞功能[59]。SMM-189治疗可通过增强p-JNK来缓解，从而改善整体牙周健康。 2.3.2 核因子κB(Nuclear Factor-κB，NF-κB)信号通路 NF-κB激活对破骨细胞形成和功能具有关键作用，大麻素和受体结合后，可以抑制NF-κB信号通路的激活，进而减少破骨细胞的形成，减少牙周炎过程中的骨吸收。ZHU等[95]发现JWH133(CB2受体激动剂)对NF-κB信号通路具有抑制作用。LIU等[96]研究发现JZL184 抑制RANKL诱导的NF-κB通路激活。此外，JZL184处理明显抑制NF-κB信号通路中p65、IκBα和IKKβ的磷酸化。MAGL敲低可抑制RANKL诱导的NF-κB和MAPK激活，降低 MAGL可抑制p65、Akt和IκB-α的磷酸化。因此在牙周炎状态下，CB2受体激活可通过抑制NF-κB信号通路抑制破骨细胞的形成和分化，减少牙槽骨的吸收。NAKAJIMA等[37]研究证明了AEA对细菌脂多糖和其他炎性细胞因子(包括单核细胞趋化蛋白1、白细胞介素8和白细胞介素1)刺激的成纤维细胞中NF-κB表达的抑制作用，所以阿难酰胺Anandamide(AEA)抑制由NF-κB途径引发的主要炎症途径。据报道，大麻素可抑制NF-κB激活，并减少NF-kB靶基因肿瘤坏死因子α和白细胞介素6的上调[97]。两种CB2受体配体显著降低了p-NF-kB，并且在整个研究过程中一直受到抑制[59]。据报道，p-ERK的增加可能通过抑制血管内皮细胞中NF-κB的激活发挥抗炎活性[98]。所以，抑制NF-κB信号通路的激活可以激发抗炎活性。由于NF-κB信号通路与骨吸收和炎症形成有关，所以抑制NF-κB信号通路可以减少牙周炎过程中牙槽骨的吸收，促进炎症愈合。炎症反应涉及细胞外到细胞内的信号传递，即信号级联反应。牙周炎还涉及到其他信号通路，但是由于与大麻素受体有关的研究相对较少，并没有展开论述，其他信号通路见表3。信号通路间关系交错纵横，同一种反应会影响不同的通路，不同的反应也会涉及同一种通路参与，所以炎症和GPCRs之间关系复杂。总之，大麻素受体作为GPCRs可以促进成骨细胞的分化和矿化，同时减少破骨细胞的数量和活性，以及可发挥抗炎活性，进而减少炎症过程中牙槽骨吸收。"

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