引用本文
钟燕婷, 杨亚军, 李嘉晓, 廖红波, 崔燎. 基于GSK-3β信号通路防治骨质疏松的天然产物作用研究进展[J]. 中国药理学通报, 2022, 38(6): 817-821.
ZHONG Yan-ting, YANG Ya-jun, LI Jia-xiao, LIAO Hong-bo, CUI Liao. Development of natural products in prevention and treatment of osteoporosis based on GSK-3β signaling pathway[J]. Chinese Pharmacological Bulletin, 2022, 38(6): 817-821.
基于GSK-3β信号通路防治骨质疏松的天然产物作用研究进展
1. 广东医科大学药学院药理学教研室，广东 湛江 524023;
2. 广东医科大学广东天然药物研究与开发重点实验室，广东 湛江 524023;
3. 华南理工大学医学院，广东 广州 510110
2. 广东医科大学广东天然药物研究与开发重点实验室，广东 湛江 524023;
3. 华南理工大学医学院，广东 广州 510110
摘要: 糖原合酶激酶-3β(glycogen synthase kinase-3β，GSK-3β)异常会引起骨代谢紊乱，导致骨质疏松，其特征是骨量丢失和骨微结构破坏，往往会增加骨折发生率。来源于植物的天然产物可以作为预防和治疗骨质疏松的潜在药物。该文综述了GSK-3β通路和骨代谢的密切联系，并阐述了黄酮类、异黄酮类、多糖和皂苷类、酚类、生物碱类、胺的衍生物类等天然产物调控GSK-3β信号通路防治骨质疏松的研究进展，为进一步开发可能有效防治骨质疏松的药物提供科学依据。
关键词:
植物 天然产物 GSK-3β 骨代谢 骨质疏松 机制
Development of natural products in prevention and treatment of osteoporosis based on GSK-3β signaling pathway
1. Dept of Pharmacology, School of Pharmacy,Guangdong Medical University,Zhanjiang Guangdong 524023, China;
2. Guangdong Key Lab for Research and Development of Nature Drugs, Guangdong Medical University, Zhanjiang Guangdong 524023, China;
3. South China University of Technology, Guangzhou 510110, China
2. Guangdong Key Lab for Research and Development of Nature Drugs, Guangdong Medical University, Zhanjiang Guangdong 524023, China;
3. South China University of Technology, Guangzhou 510110, China
Abstract: Abnormality of glycogen synthase kinase-3 β (GSK-3β) triggers a deleterious consequence of disorder of bone metabolism, contributing to osteoporosis. Osteoporosis is characterized by bone loss and destruction of bone microstructure, which often leads to the increase of incidence rate of fracture. Natural products derived from plants can be used as potential drugs to prevent and treat osteoporosis. In this review, we elaborates on the intimate connection between GSK-3β and bone metabolism, and summarizes natural products of flavonoids, isoflavones, pol-ysaccharides and saponins, phenols, alkaloids and amine derivatives regulating GSK-3β pathway in the prevention and treatment of osteoporosis, which may provide scientific evidence for further development of drugs that may effectively prevent and treat osteoporosis.
Key words:
plants natural products GSK-3β bone metabolism osteoporosis mechanism
骨代谢是通过骨形成和骨吸收活动维持骨量和骨质量的动态平衡过程。该平衡被打破，就会引起骨代谢疾病，最常见的是骨质疏松。全世界有超过2亿人患有骨质疏松。雌激素缺乏、衰老、药物、不良生活方式等因素常常会引起骨代谢疾病，导致骨质疏松。促骨形成药和抗骨吸收药是当前最常见的两大类抗骨质疏松药物。双磷酸盐类等抗骨吸收药通过抑制破骨细胞活性，显著减少骨质流失，但存在恶心、呕吐、消化不良等不良反应，甚至颌骨坏死[1]；特立帕肽等促骨形成药通过刺激骨形成，显著增加骨量，提高骨强度，但价格昂贵成为了该药的瓶颈。Wnt/β-catenin是调节骨发育和骨代谢过程的重要信号通路[2]，而糖原合酶激酶-3β(glycogen synthase kinase-3β，GSK-3β)作为Wnt信号通路的下游靶点，其对骨代谢的调节作用也逐渐受到重视。目前，从植物中提取天然产物是一个研究热点。来源于植物的天然产物是一类具有不同结构的次生代谢物，具有多种活性成分和药理作用，可作为传统药物用于预防和治疗各种疾病。本文就天然产物如何通过GSK-3β信号通路调节对骨代谢疾病的潜在作用进行综述。
1 GSK-3β对骨代谢的作用骨代谢是通过成骨细胞负责的骨形成和破骨细胞负责的骨吸收进行骨转换的一种新陈代谢过程。影响调节骨代谢的信号通路，就会影响骨代谢的发生和发展。GSK-3β作为一种骨代谢的负性调节因子，它主要通过磷酸化的方式来调控骨代谢疾病。GSK-3β氨基端的丝氨酸-9(ser-9)磷酸化后会抑制酶活性，促进骨形成；而酪氨酸-216(tyr-216)的磷酸化则增强其活性，抑制骨生成[3]。因此，有必要分析GSK-3β与成骨细胞和破骨细胞之间的联系，详细阐明其对骨代谢的影响。
1.1 GSK-3β与成骨细胞GSK-3β对成骨细胞的形成具有抑制作用。据报道，GSK-3β通过介导成骨细胞线粒体的凋亡，诱发股骨头坏死[3]，这是引发骨质疏松的1个独立风险因素。此外，GSK-3β可以影响其他细胞因子的生理作用，进而调控成骨分化功能。当GSK-3β受到抑制时，通过刺激BMP信号通路降低硬化蛋白(sclerostin)的表达，可进一步促进成骨细胞的分化[4]。另据报道，来源于骨髓成骨细胞和脂肪细胞的脂联素受体1(AdipoR1)，其过表达可以触发GSK-3β信号通路，进而调控小鼠的成骨细胞分化，增加骨密度[5]。目前，在成骨细胞的形成、分化和骨形成活动当中，GSK-3β如何调控骨代谢过程当中的信号通路，是否GSK-3β与前述上下游的信号分子相互作用并抑制骨形成活动，尚需进一步的研究。
1.2 GSK-3β与破骨细胞破骨细胞是一类多核巨噬细胞，由单核/巨噬细胞系前体通过一系列的增殖、分化、融合而成，具有骨吸收功能。GSK-3β在破骨细胞诱导和分化的过程中亦至关重要。据报道，在核因子κB受体活化因子配体(receptor activator of nuclear factor-κB ligand, RANKL)诱导破骨细胞分化过程中，PI3K/Akt介导的GSK-3β(Ser9)磷酸化后以ERK依赖方式引发异质核内核糖核蛋白K(hnRNPK)的核质易位，增强GSK-3β和hnRNPK的胞质共定位和相互作用，而hnRNPK基因的敲除是导致破骨细胞吸收能力丧失的重要原因[6]。众所周知，成骨细胞通过骨保护素(osteoprotegerin, OPG)/RANKL信号通路调控破骨细胞的形成与功能。然而，是否GSK-3β将成骨细胞与破骨细胞联系起来完成骨重建活动，是否GSK-3β可以作为抗骨质疏松的药靶，目前尚不清楚。
2 GSK-3β抑制剂对骨代谢相关疾病的影响目前，科研工作者对GSK-3β抑制剂的研究取得了一些进展。锂(Li)是最早被发现的一种GSK-3β抑制剂。据报道，氯化锂(LiCl)对类风湿性关节炎(rheumatoid arthritis, RA)患者产生的炎症介质具有抑制作用，但其抗炎作用的确切机制尚不清楚[7]。在脂多糖和甲基泼尼松龙诱导的大鼠股骨头非创伤性骨坏死模型中，LiCl能有效抵抗GSK3β (ser-9)磷酸化的降低和成骨细胞的凋亡[8]。此外，6-溴靛二脲-3′-肟(BIO)[9]和GSK-3β抑制剂能够提高成骨分化能力，增强骨密度，促进骨重建[10]。综上所述，GSK-3β抑制剂对骨代谢相关疾病具有良好的防治作用，它们有可能直接防治骨质疏松，也有可能通过改善原发病的症状治疗继发性骨质疏松。
3 天然产物通过调控GSK-3β信号通路防治骨质疏松骨质疏松是一种慢性代谢性疾病，平衡成骨细胞和破骨细胞是维持骨骼健康的必要条件。来源于植物的天然产物主要包括黄酮类、异黄酮类、多糖和皂苷类、酚类、生物碱类、胺的衍生物类等。该类化合物因具有强抗氧化性和抗炎作用，可以通过GSK-3β信号通路，有效调节骨代谢相关指标，进而发挥抗骨质疏松作用。具体机制如下：一方面，天然产物主要通过诱导(ser9位点)或抑制(tyr216位点)GSK-3β磷酸化，使核内β-连环蛋白聚积，进而促进成骨细胞的增殖、分化或抑制破骨细胞的生成；另一方面，天然产物通过抑制与GSK-3β相关的氧化损伤和神经元以增强成骨活性，或以雌激素依赖方式激活GSK-3β信号转导以促进成骨，从而达到防治骨质疏松的作用。骨代谢相关指标是代表成骨细胞和破骨细胞活性的相关离子、分子及其调控激素，主要包括骨形成标志物(COL-I、Runx2、OSX、OCN、BMP2、ALP、OPN、OPG等)和骨吸收标志物(RANKL、CTSK、DC-STAMP、NFATc1、TRAF6、TRAP等)两大类，它们对维持骨动态平衡具有重要意义。以下将以表格形式列举各类天然产物与GSK-3β和骨质疏松的密切联系(Tab 1)。
Tab 1 Origin, classification and pharmacological effects of natural products
| Natural products | Origin | Species | In vivo/In vitro | Model | Administration | Dose/ Time | Bone metabolic index | Mechanism | Diseases | References |
| Flavonoids | Greenpepper，celery，perillaleaf | Luteolin | in vitro;in vivo | MC3T3-E1; Dex-induced OP rats | intragastric | 0.05~0.2μmol·L-1; 25~100 mg·kg-1 for 60days | ↑OPG/RANKL，↑Runx2，↑OSX，↑Col-I | LUT suppressed oxidative injury to promote osteo-blastic proliferation and enhanced osteoblastic ac- tivities to maintain bone mass in GIOP via the GSK-3β pathways. | GIOP | [11] |
| Herba epimedii | Icariin | in vitro;in vivo | SaoS2; PDS-in- duced OP mice | oral | 10-6~10-9 mol·L-1; 250 mg·kg-1 for 60 days | ↑Runx2 | Icariin protected bone formation by increasing p-GSK-3β at ser9. | GIOP | [12] | |
| Apple peels | Phlorizin and phlor- etin | in vitro;in vivo | MC3T3E1; SAMP6 mice | oral | 1~20 μmol· L-1; 10 mg·kg-1 for 14 weeks | ↑TRAF，↑BMP2，↑Col-I，↓CTSK. ↑OPG/RANKL，↑ Runx2，OCN | Phlorizin and phloretin promoted osteoblast for- mation and improved bone mineralization of fe- mur，tibia，and vertebra by inhibiting GSK-3β neurons. | SOP | [13] | |
| apples，grapes，strawber- ries | Fisetin | in vitro;in vivo | MC3T3-E1; PDS-in- duced OP zebrafish | medicated bath | 0~1 000 nmol ·L-1; 0~ 200 μmol· L-1，once ev- ery two days for 4 days | ↑Runx2，↑ALP, ↑Col-I，↑OSX, ↑ OCN，↑BMP4, ↓ DC-STAMP, ↓NFATc1, ↓TRAP6, ↓CTSK | Fisetin stimulated p- GSK-3β at Ser9，thereby upregulating osteoblast differentiation and stimu- lating bone formation；it also alleviates PDS-in- duced bone resorption by inhibiting the expression of osteoclasts-related genes. | GIOP | [14] | |
| Isoflavone | Daphnetin | Daphnetin | in vitro;in vivo | MC3T3- E1;Dex- induced OP rats | - | 0~80 μmol· L-1; 1~4 mg ·kg-1 for 8 weeks | ↑BMP2，↑Col-I，↑Runx2，↑OSX，↑OPN，↑ALP | Daphnetin has a protec- tive effect on Dex-in- duced osteoporosis，fur- ther improving bone mass，bone microstruc- ture and bone homeosta- sis by promoting p-GSK- 3β. | OP | [15] |
| Caesal-piniasappan L. | Sap- panone A | in vitro;in vivo | BMMs; LPS-in- duced bone loss mice | intraperito- neal injec- tion | 0~30 μmol· L-1; 50 mg· kg-1 once ev- ery two days for 8 days | ↓DC-STAMP，↓ NFATc1，↓ TRAP6，↓CTSK | Sappanone A inhibited RANKL-induced osteo- clast formation through GSK-3β pathway. | OP | [16] | |
| Psoraleacorylifolia L. | Psoralidin | in vitro | BMSCs，MC3T3- E1 | - | 0.001~20 μmol·L-1 | ↑Runx2，↑OSX，↑BSP，↑OCN | Psoralidin activated GSK- 3β signal transduction and phosphorylated GSK- 3β to promote osteogene- sis in an estrogen-de- pendent manner. | PMOP | [17] | |
| Fagara | Sesamin | in vitro;in vivo | BMSCs; OVX rats | intragastric | 1~10 μmol· L-1; 80 mg· kg-1 for 12 weeks | ↑SOX9，↑OCN，↑Runx2，↑Col-I，↑ALP，↑OSX | Sesamin effectively pro- moted osteogenic differ- entiation of BMSCs by down-regulating the GSK- 3β in an concentrated- dependent manner. | PMOP | [18] | |
| Polysaccha- rides and saponins | Polygona- tum sibir- icum | PSP | in vitro | BMSCs | - | 0~25 mg· L-1 | ↓siRNA：Runx2，ALP，OCN | PSP promoted osteoblast differentiation and miner- alization in vitro by de- creasing GSK-3β levels. | OP | [19] |
| Rehman- nia gluti- nosa | RRP aqueous extract | in vivo | OVX rats | intragastric | 2.5 g/mL/100 g for 14 weeks | ↑OPG，↓TRAP, ↓ALP，↓DKK1，↓SOST，↓CTSK，↓RANKL, ↑Runx2 | RRP total polysaccharide increased cortical and epiphyseal thickness and improved bone trabecular distribution by up-regula- ting p-GSK-3β/GSK-3β ratio. | PMOP | [20] | |
| Cistanche desertico- la | Cistanche deserticola total gly- cosides and poly- saccha- rides | in vitro | SAMP6 mice | intragastric | 400 mg·kg-1 for 12 weeks | ↑BMP-2，↑OCN，↓RANKL，↑OPG | Total glycosides and pol- ysaccharides in C. deser- ticola changed bone con- version biomarkers，pro- moted new bone forma- tion，and accelerated calcium deposition by up- regulating p-GSK-3β (Ser9). | OP | [21] | |
| Astragalus | Astragalo- side Ⅳ | in vitro | BMSCs | - | 0~40 μmol· L-1 | ↑OSX，↑Runx2，↑OCN，↑OPN | AST promoted differentia- tion of hBMSCs by GSK- 3β signaling pathway. | OP | [22] | |
| Phenols | Guava | UA and 2α-UA | in vitro;in vivo | OBs; OVX rats | oral | 0.1~2 g· L-1; 250 mg· kg-1 for 16 weeks | ↑BMP-2，↑Col-I，↑Runx2 | UA and 2α-UA were stimulate bone regenera- tion and restore bone loss and bone anabolism by phosphorylating GSK-3β. | PMOP | [23] |
| Hibiscus syriacus L. | AHs | in vitro;in vivo | MC3T3E1，MG-63; PDS-in- duced OP zebrafish | medicated bath | 0~400 mg· L-1; 0~200 mg·L-1 for 6 days | ↑OSX，↑ALP，↑ RUNX2 | AHs stimulated osteogen- ic activity and produces anti-osteoporosis effects by phosphorylation of GSK-3β at ser9. | GIOP | [24] | |
| Piper betleleav- es | HCV | in vitro;in vivo | C3H10T1/ 2;Dex-in- duced OP rats | intragastric | 125~4 000 μg ·L-1; 1 mg· kg-1 once ev- ery two days for 6 weeks | ↑Runx2，↑OPN | HCV increased Runx2 and osteopontin expres- sion，stimulating osteo- genesis and restoring bone mass and tissue mi- crostructure by GSK-3β signaling pathway. | GIOP | [25] | |
| Alkaloids | Ligusticum wallichii | Ligus- trazine | in vitro | BMMs | - | 0~50 mg· L-1 | ↑CTSK，↑CTR, ↑DC-STAMP, ↑TRAP，↑NFATc1 | Ligustrazine promoted RANKL-induced osteo- clast differentiation and bone resorption by phos- phorylating GSK-3β. | OP | [26] |
| Derivatives of amines | Maca | MBOC | in vitro;in vivo | C3H10T1/ 2;OVX mice | oral | 0~100 μmol ·L-1; 20 mg ·kg-1 for 30 days | ↑Runx2，↑OSX，↑OCN | MBOC activated osteo- genic differentiation，stimulated bone forma- tion，and increased os- teocalcin and Runx2 lev- els by inhibiting p-GSK- 3β at tyr216. | PMOP | [27] |
| Others | FLL dried ripen fruit | FLL a- queous extraction | in vitro;in vivo | OBs; OVX rats | oral | 1%~10%; 3.5 g·kg-1 for 12 weeks | ↑OPG，↓CTSK，↑PINP，↓CTx-1，↑ALP，↑RUNX2，↓SOST，↓DKK1，↓sRANKL，↓TRAP5b | FLL aqueous extraction promoted osteoblast bone formation and protected the bone quality of OVX rats by up-regulating p- GSK-3β. | PMOP | [28] |
| Dex，dexamethasone; PDS，prednisolone; GIOP，glucocorticoid-induced osteoporosis; SAMP6，senescence accelerated mice-prone; SOP，senile osteoporosis; OP，osteoporosis; PMOP，postmenopausal osteoporosis; LPS，lipopolysaccharide; PSP，polygonatum sibiricum polysaccharide; RRP，Rehmanniae Radix Preparata; UA，ursolic acid; 2α-UA，2α-hydroxy ursolic acid; AHs，anthocyanin-enriched polyphenols from Hibiscus syriacus L.; HCV，the major phenolic constituent(hydroxychavicol)of Piper betleleaves; hBMSCs，human bone marrow mesenchymal stem cells; MBOC，N-(3-methoxybenzyl)-(9Z，12Z，15Z)-octadecatrienamide，is one of the macamides isolated from Maca; FLL，Fructus Ligustri Lucidi | ||||||||||
骨质疏松是一种危害骨骼健康的慢性疾病，抗骨质疏松药物的开发日益成为了国内外研究的热点。来源于植物的天然产物是一类具有多种药理作用的活性成分，大量研究证明，植物药物有良好的抗骨质疏松作用，它们在体内和体外主要通过调控成骨细胞和破骨细胞之间的平衡，实现对骨质疏松的防治作用。黄酮类、异黄酮类、多糖和皂苷类、酚类、生物碱类、胺的衍生物类等天然产物防治骨质疏松的靶点众多，GSK-3β信号通路是其中之一。在机制上，GSK-3β引起的磷酸化可能是天然产物调控骨质疏松发病的一个重要因素，促进GSK-3β ser9位点的磷酸化可以刺激骨形成，反之，触发GSK-3β tyr216位点的磷酸化会导致骨吸收。此外，GSK-3β抑制剂同样具有对抗骨质疏松的潜力。因此，来源于植物的天然产物和GSK-3β信号通路有望成为防治骨质疏松的新靶点。随着研究的不断深入，有必要深入研究天然产物的药效学、毒理学和构效关系，以便进入临床用于骨质疏松的治疗。
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