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Article(id=1198619428347802191, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198619422425448948, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2279.2023.0620, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1667404800000, receivedDateStr=2022-11-03, revisedDate=null, revisedDateStr=null, acceptedDate=1677427200000, acceptedDateStr=2023-02-27, onlineDate=1763702740990, onlineDateStr=2025-11-21, pubDate=1716825600000, pubDateStr=2024-05-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763702740990, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763702740990, creator=13701087609, updateTime=1763702740990, updator=13701087609, issue=Issue{id=1198619422425448948, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='5', pageStart='489', pageEnd='610', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763702739578, creator=13701087609, updateTime=1763702927730, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198620211667628088, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198619422425448948, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198620211667628089, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198619422425448948, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=578, endPage=585, ext={EN=ArticleExt(id=1198619429878723197, articleId=1198619428347802191, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research advances in signal pathways related to active components of Psoralea corylifolia in osteoporosis, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Osteoporosis (OP) is a systemic bone disease characterized by low bone mass and damage to the microstructure of bone tissue, leading to increased bone fragility and susceptibility to fracture. Owing to its high prevalence, disability and mortality rates, as well as more sequelae, it brings heavy burden to patients and society. In recent years, as the research on the chemical and pharmacological effects of Psoralea corylifolia has made great progress, scholars have isolated compounds such as coumarins, flavonoids and monoterpene phenols, which have anti-OP, anti-oxidation, and anti-inflammatory properties, Psoralea corylifolia has been widely used in the treatment of OP. This article reviews the regulatory mechanism of active ingredients of Psoralea corylifolia in OP lipid metabolism, bone metabolism and oxidative stress, as well as related therapeutic strategies targeting Wnt/β-catenin, PI3K/Akt, PPAR-γ/Wnt, RANKL/RANK/MAPK and NF-κB signaling pathways, in order to provide further reference for the prevention and treatment of OP.

, correspAuthors=Xiao-Yun Zhang, authorNote=null, correspAuthorsNote=
E-mail:
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骨质疏松症(OP)是一种以骨量低下、骨组织微结构损坏，导致骨脆性增加、易发生骨折为特征的全身性骨病，不仅患病率、致残率、病死率高，且后遗症多，给患者及社会带来沉重负担。随着补骨脂(Psoralea corylifolia)的化学及药理作用研究取得长足进展，从中分离出的香豆素类、黄酮类和单萜酚类等化合物，具有抗OP、抗氧化、抗炎等作用，已被广泛用于OP治疗中。本文针对补骨脂活性成分在OP脂质代谢、骨代谢和氧化应激中的调节作用机制，以及以Wnt/β-catenin、PI3K/Akt、PPAR-γ/Wnt、RANKL/RANK/MAPK、NF-κB信号通路为靶点的相关治疗策略进行综述，以期为OP的预防和治疗提供参考。

, correspAuthors=章晓云, authorNote=null, correspAuthorsNote=
章晓云，E-mail：
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武瑞骐，硕士研究生，主要从事脊柱、骨关节创伤性疾病的中医防治研究

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武瑞骐，硕士研究生，主要从事脊柱、骨关节创伤性疾病的中医防治研究

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武瑞骐，硕士研究生，主要从事脊柱、骨关节创伤性疾病的中医防治研究

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OP. 骨质疏松症；Wnt/β-catenin. Wnt/β-连环蛋白；PI3K. 磷脂酰肌醇-3-激酶；Akt. 蛋白激酶B；GSK-3β. 糖原合成激酶3β；Nrf2. 核因子E2相关因子2；PPAR-γ. 过氧化物酶体增殖物激活受体-γ；Axin2. 支架蛋白；ROS. 活性氧；Keapl. Kelch环氧氯丙烷相关蛋白1；ER. 雌激素受体；LRP5/6. 低密度脂蛋白5或6；TCF/LEF. T细胞因子/淋巴增强子因子；FoxO3a. 叉头框转录因子O3a

, figureFileSmall=6sFc0nMvVEUuh4CJBaAIzQ==, figureFileBig=cRhEvKnVreVIfHlQ+1duIg==, tableContent=null), ArticleFig(id=1198630237278929868, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619428347802191, language=EN, label=Fig.2, caption=Mechanism of action of active components of Psoralea corylifolia mediating RANKL/RANK/MAPK and NF‑κB signaling pathways against osteoporosis, figureFileSmall=/5KFtOYsREetSdLlCqvk7w==, figureFileBig=JDQ1nDFuAxTwQcGNB5BBGQ==, tableContent=null), ArticleFig(id=1198630237379593166, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619428347802191, language=CN, label=图2, caption=补骨脂活性成分介导RANKL/RANK/MAPK、NF-κB信号通路抗OP的作用机制

OP. 骨质疏松症；RANKL. 核因子-κB受体活化因子配体；RANK. 核因子-κB受体活化因子；p38. p38激酶；JNK. C-Jun N末端激酶；ERK. 细胞外信号调节激酶；p50/p65. 细胞核因子-κB的二聚体；TRAF6. 肿瘤坏死因子受体相关蛋白6；TRACP. 抗酒石酸酸性磷酸酶；MAPK. 三种丝裂原活化蛋白激酶；IκBα. 核因子κB抑制因子A；NFATc1. 破骨细胞核因子；c-Fos. 破骨细胞转录因子

, figureFileSmall=/5KFtOYsREetSdLlCqvk7w==, figureFileBig=JDQ1nDFuAxTwQcGNB5BBGQ==, tableContent=null), ArticleFig(id=1198630237450896335, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619428347802191, language=EN, label=Tab.1, caption=

The main and specific components in Psoralea corylifolia

, figureFileSmall=null, figureFileBig=null, tableContent=
主要成分类型特异性成分化合物名称化学式
香豆素类
呋喃香豆素类补骨脂素(Psoralen)C11H6O3
异补骨脂素(Isopsoralen)C11H6O3
拟雌内酯类补骨脂定(Psoralidin)C20H16O5
其他
黄酮类
二氢黄酮类补骨脂二氢黄酮(Bavachin)C19H19O4
补骨脂二氢黄酮甲醚(Bavachinin)C20H21O4
异补骨脂二氢黄酮(Isobavachin)C20H19O4
异黄酮类新补骨脂异黄酮(Neobavaisoflavone)C20H18O4
补骨脂异黄酮(Corylin)C20H16O4
Corylifol AC25H26O4
查尔酮类异补骨脂查尔酮(Isobavachalcone)C20H20O4
黄酮醇类AstragalinC21H20O11
其他
单萜酚类补骨脂酚(Bakuchiol)C18H24O
Psoracorylifol AC18H24O3
Psoracorylifol FC18H24O2
), ArticleFig(id=1198630237534782417, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619428347802191, language=CN, label=表1, caption=

补骨脂中主要成分类型及特异性成分

, figureFileSmall=null, figureFileBig=null, tableContent=
主要成分类型特异性成分化合物名称化学式
香豆素类
呋喃香豆素类补骨脂素(Psoralen)C11H6O3
异补骨脂素(Isopsoralen)C11H6O3
拟雌内酯类补骨脂定(Psoralidin)C20H16O5
其他
黄酮类
二氢黄酮类补骨脂二氢黄酮(Bavachin)C19H19O4
补骨脂二氢黄酮甲醚(Bavachinin)C20H21O4
异补骨脂二氢黄酮(Isobavachin)C20H19O4
异黄酮类新补骨脂异黄酮(Neobavaisoflavone)C20H18O4
补骨脂异黄酮(Corylin)C20H16O4
Corylifol AC25H26O4
查尔酮类异补骨脂查尔酮(Isobavachalcone)C20H20O4
黄酮醇类AstragalinC21H20O11
其他
单萜酚类补骨脂酚(Bakuchiol)C18H24O
Psoracorylifol AC18H24O3
Psoracorylifol FC18H24O2
), ArticleFig(id=1198630237610279891, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619428347802191, language=EN, label=Tab.2, caption=

Study model and mechanism of psoralen coumarins in the treatment of osteoporosis

, figureFileSmall=null, figureFileBig=null, tableContent=
活性成分受试对象作用机制
补骨脂素双卵巢切除法建立OP大鼠模型[7]激活Wnt/β-catenin信号通路，成骨细胞分化↑
补骨脂定小鼠骨髓巨噬细胞[9]TNF-α、RANK/OPG↓，抑制p38、JNK和ERK，破骨细胞分化↓
补骨脂素小鼠骨骼干细胞[10]激活PI3K/Akt信号通路，GSK-3β、Nrf2↑，抗氧化应激
补骨脂定双卵巢切除法建立OP大鼠模型[11]ROS↓，骨保护作用
补骨脂定大鼠颅骨中分离出成骨细胞[12]激活ER信号通路，抗氧化应激，OP↓
异补骨脂素双卵巢切除法建立OP大鼠模型[13]调节PPAR-γ/Wnt信号通路，PPAR-γ↓
异补骨脂素肌注地塞米松钠注射液建立OP大鼠模型[14]抑制Axin2/PPAR-γ信号通路，骨髓脂质代谢↓，成骨细胞分化↑
异补骨脂素羧甲基纤维素钠灌胃建立OP大鼠模型[15]抑制FoxO3a信号通路，ROS↓，成骨细胞分化↑
异补骨脂素双卵巢切除法建立OP大鼠模型[16]调节PPAR-γ/Wnt通路，抗氧化应激
补骨脂素小鼠破骨细胞前体细胞[17]抑制RANKL、M-CSF和RANK诱导的破骨细胞分化↓
异补骨脂素双卵巢切除法建立OP大鼠模型[18]骨小梁数目↑，膜内骨化和小梁骨面积↑
), ArticleFig(id=1198630237736109015, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619428347802191, language=CN, label=表2, caption=

补骨脂香豆素类化合物治疗OP的研究模型及作用机制

, figureFileSmall=null, figureFileBig=null, tableContent=
活性成分受试对象作用机制
补骨脂素双卵巢切除法建立OP大鼠模型[7]激活Wnt/β-catenin信号通路，成骨细胞分化↑
补骨脂定小鼠骨髓巨噬细胞[9]TNF-α、RANK/OPG↓，抑制p38、JNK和ERK，破骨细胞分化↓
补骨脂素小鼠骨骼干细胞[10]激活PI3K/Akt信号通路，GSK-3β、Nrf2↑，抗氧化应激
补骨脂定双卵巢切除法建立OP大鼠模型[11]ROS↓，骨保护作用
补骨脂定大鼠颅骨中分离出成骨细胞[12]激活ER信号通路，抗氧化应激，OP↓
异补骨脂素双卵巢切除法建立OP大鼠模型[13]调节PPAR-γ/Wnt信号通路，PPAR-γ↓
异补骨脂素肌注地塞米松钠注射液建立OP大鼠模型[14]抑制Axin2/PPAR-γ信号通路，骨髓脂质代谢↓，成骨细胞分化↑
异补骨脂素羧甲基纤维素钠灌胃建立OP大鼠模型[15]抑制FoxO3a信号通路，ROS↓，成骨细胞分化↑
异补骨脂素双卵巢切除法建立OP大鼠模型[16]调节PPAR-γ/Wnt通路，抗氧化应激
补骨脂素小鼠破骨细胞前体细胞[17]抑制RANKL、M-CSF和RANK诱导的破骨细胞分化↓
异补骨脂素双卵巢切除法建立OP大鼠模型[18]骨小梁数目↑，膜内骨化和小梁骨面积↑
), ArticleFig(id=1198630237815800794, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619428347802191, language=EN, label=Tab.3, caption=

Study model and mechanism of Psoralea corylifolia flavonoids on osteoporosis

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化学成分受试对象作用机制
新补骨脂异黄酮地塞米松处理小鼠颅尖成骨细胞MC3T3-E1[20]激活Nrf2/HO-1信号通路，成骨细胞分化↑，抗氧化应激
补骨脂异黄酮大鼠颅骨中分离出成骨细胞[21]激活Wnt/β-catenin信号通路，Runx2↑，Osterix↑，成骨细胞分化↑
补骨脂二氢黄酮双卵巢切除法建立OP大鼠模型[22]激活Wnt/β-catenin信号通路，LRP5↑，β-catenin↑，成骨细胞分化↑
新补骨脂异黄酮双卵巢切除法建立OP大鼠模型[23]抑制NF-κB信号通路，破骨细胞分化↓
补骨脂二氢黄酮甲醚小鼠骨髓中分离破骨细胞[24]抑制NF-κB信号通路，Akt、p38、JNK、ERK↓，破骨细胞分化↓
补骨脂异黄酮双卵巢切除法建立OP大鼠模型[25]抑制NF-κB信号通路，破骨细胞分化↓
), ArticleFig(id=1198630237895492575, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619428347802191, language=CN, label=表3, caption=

补骨脂黄酮类化合物治疗OP的研究模型及作用机制

, figureFileSmall=null, figureFileBig=null, tableContent=
化学成分受试对象作用机制
新补骨脂异黄酮地塞米松处理小鼠颅尖成骨细胞MC3T3-E1[20]激活Nrf2/HO-1信号通路，成骨细胞分化↑，抗氧化应激
补骨脂异黄酮大鼠颅骨中分离出成骨细胞[21]激活Wnt/β-catenin信号通路，Runx2↑，Osterix↑，成骨细胞分化↑
补骨脂二氢黄酮双卵巢切除法建立OP大鼠模型[22]激活Wnt/β-catenin信号通路，LRP5↑，β-catenin↑，成骨细胞分化↑
新补骨脂异黄酮双卵巢切除法建立OP大鼠模型[23]抑制NF-κB信号通路，破骨细胞分化↓
补骨脂二氢黄酮甲醚小鼠骨髓中分离破骨细胞[24]抑制NF-κB信号通路，Akt、p38、JNK、ERK↓，破骨细胞分化↓
补骨脂异黄酮双卵巢切除法建立OP大鼠模型[25]抑制NF-κB信号通路，破骨细胞分化↓
), ArticleFig(id=1198630238071653346, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619428347802191, language=EN, label=Tab.4, caption=

Study model and mechanism of Psoralea corylifolia monoterpene phenols in treating osteoporosis

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化学成分受试对象作用机制
补骨脂酚大鼠颅骨中分离出成骨细胞[21]激活Wnt/β-catenin信号通路，成骨细胞分化↑
补骨脂酚小鼠性激素缺乏建立OP模型[27]骨小梁数目↑，膜下生骨↑，骨小梁间隙↓
补骨脂酚泼尼松龙处理建立斑马鱼OP模型[28]骨密度↑，骨骼发育钙化↑
), ArticleFig(id=1198630238147150821, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619428347802191, language=CN, label=表4, caption=

补骨脂单萜酚类化合物治疗OP的研究模型及作用机制

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化学成分受试对象作用机制
补骨脂酚大鼠颅骨中分离出成骨细胞[21]激活Wnt/β-catenin信号通路，成骨细胞分化↑
补骨脂酚小鼠性激素缺乏建立OP模型[27]骨小梁数目↑，膜下生骨↑，骨小梁间隙↓
补骨脂酚泼尼松龙处理建立斑马鱼OP模型[28]骨密度↑，骨骼发育钙化↑
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补骨脂活性成分治疗骨质疏松症的相关信号通路的研究进展
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武瑞骐 1, 2 , 章晓云 1, * , 杨启培 1, 2 , 彭清林 1, 2
解放军医学杂志 | 综述 2024,49(5): 578-585
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解放军医学杂志 | 综述 2024, 49(5): 578-585
补骨脂活性成分治疗骨质疏松症的相关信号通路的研究进展
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武瑞骐1, 2, 章晓云1, * , 杨启培1, 2, 彭清林1, 2
作者信息
  • 1广西中医药大学附属瑞康医院骨科，广西南宁 530011
  • 2广西中医药大学研究生院，广西南宁 530001

    • 武瑞骐，硕士研究生，主要从事脊柱、骨关节创伤性疾病的中医防治研究

通讯作者:

章晓云，E-mail：
Research advances in signal pathways related to active components of Psoralea corylifolia in osteoporosis
Rui-Qi Wu1, 2, Xiao-Yun Zhang1, * , Qi-Pei Yang1, 2, Qing-Lin Peng1, 2
Affiliations
  • 1Department of Orthopaedics, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530011, China
  • 2Graduate School of Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530001, China
出版时间: 2024-05-28 doi: 10.11855/j.issn.0577-7402.2279.2023.0620
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摘要
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骨质疏松症(OP)是一种以骨量低下、骨组织微结构损坏，导致骨脆性增加、易发生骨折为特征的全身性骨病，不仅患病率、致残率、病死率高，且后遗症多，给患者及社会带来沉重负担。随着补骨脂(Psoralea corylifolia)的化学及药理作用研究取得长足进展，从中分离出的香豆素类、黄酮类和单萜酚类等化合物，具有抗OP、抗氧化、抗炎等作用，已被广泛用于OP治疗中。本文针对补骨脂活性成分在OP脂质代谢、骨代谢和氧化应激中的调节作用机制，以及以Wnt/β-catenin、PI3K/Akt、PPAR-γ/Wnt、RANKL/RANK/MAPK、NF-κB信号通路为靶点的相关治疗策略进行综述，以期为OP的预防和治疗提供参考。

补骨脂  /  骨质疏松症  /  氧化应激  /  骨吸收  /  信号通路

Osteoporosis (OP) is a systemic bone disease characterized by low bone mass and damage to the microstructure of bone tissue, leading to increased bone fragility and susceptibility to fracture. Owing to its high prevalence, disability and mortality rates, as well as more sequelae, it brings heavy burden to patients and society. In recent years, as the research on the chemical and pharmacological effects of Psoralea corylifolia has made great progress, scholars have isolated compounds such as coumarins, flavonoids and monoterpene phenols, which have anti-OP, anti-oxidation, and anti-inflammatory properties, Psoralea corylifolia has been widely used in the treatment of OP. This article reviews the regulatory mechanism of active ingredients of Psoralea corylifolia in OP lipid metabolism, bone metabolism and oxidative stress, as well as related therapeutic strategies targeting Wnt/β-catenin, PI3K/Akt, PPAR-γ/Wnt, RANKL/RANK/MAPK and NF-κB signaling pathways, in order to provide further reference for the prevention and treatment of OP.

Psoralea corylifolia  /  osteoporosis  /  oxidative stress  /  bone resorption  /  signal pathway
武瑞骐, 章晓云, 杨启培, 彭清林. 补骨脂活性成分治疗骨质疏松症的相关信号通路的研究进展. 解放军医学杂志, 2024 , 49 (5) : 578 -585 . DOI: 10.11855/j.issn.0577-7402.2279.2023.0620
Rui-Qi Wu, Xiao-Yun Zhang, Qi-Pei Yang, Qing-Lin Peng. Research advances in signal pathways related to active components of Psoralea corylifolia in osteoporosis[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (5) : 578 -585 . DOI: 10.11855/j.issn.0577-7402.2279.2023.0620
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骨质疏松症(osteoporosis，OP)是以骨量减少和骨组织微结构破坏为主要表现的一类疾病，易导致骨骼强度下降和骨折风险增加[1-2]。据流行病学调查显示，在50岁及以上人群中，男性患病率为6.46%，而女性由于绝经后雌激素分泌减少，患病率上升至29.13%；OP不仅降低患者生命质量，且由于其高致残率和高病死率，给患者及社会造成了沉重的经济负担[3]。目前抗OP药物主要以双膦酸盐、降钙素、选择性雌激素受体调节剂为主，虽有成效，但存在胃肠道反应、鼻出血和深静脉血栓形成风险增加等不良反应，因此寻求一种不良反应少且安全性高的药物治疗方案尤为重要。
中医药治疗OP具有骨保护作用、成本低、不良反应少等优势。中药补骨脂(Psoralea corylifolia)是豆科植物补骨脂的干燥成熟果实，性味苦、辛、温，归脾、肾经，具有补肾助阳、纳气平喘之功，是治疗骨质减少及骨折的经典草药之一。既往研究发现，补骨脂的提取物和化学成分具有促进骨生成的能力，可抑制骨吸收[4-5]。目前，补骨脂多应用于许多经典配方中，如仙灵骨葆胶囊、二仙汤等，但其活性成分的作用机制鲜少报道。本文总结近年来补骨脂活性成分在OP治疗中的分子机制和相关信号通路，综述其通过诱导氧化应激、调节成骨和破骨细胞的分化或活化以及调节脂质代谢而发挥抗OP的作用，以期为OP的基础和临床深入研究提供参考。
1 补骨脂活性成分治疗OP相关研究
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现代药理学研究发现，从补骨脂中分离出的活性成分主要以香豆素类、黄酮类及单萜酚类三大类化合物为主(表1)。它们是补骨脂治疗的物质基础，具有抗OP、抗氧化、抗炎症、调节雌激素水平等多种药理作用。近年来研究发现，补骨脂活性成分可调控OP多种信号通路相关靶蛋白的表达，是目前OP药物防治领域的热点。
1.1 香豆素类化合物
香豆素是一类具有芳香气味的天然化合物，在自然界中广泛存在于苯苄α-吡喃酮的母环结构中。目前，有学者从补骨脂香豆素类化合物中分离得到呋喃香豆素类、拟雌内酯类等化合物[6]。从呋喃香豆素类中分离出的主要活性成分为补骨脂素(Psoralen)和异补骨脂素(Isopsoralen)，可在OP、肿瘤和炎症治疗中起重要作用。目前研究发现，在双卵巢切除OP大鼠模型中，补骨脂素通过激活Wnt/β-连环蛋白(β-catenin)信号通路能够有效调节骨形成和骨吸收过程，保护骨组织[7]；异补骨脂素通过上调成骨特异性转录因子(Runx2) mRNA和蛋白的表达、下调基质金属蛋白酶13(MMP-13) mRNA和蛋白的表达，从而明显增加OP大鼠骨密度[8]；此外，研究发现，拟雌内酯类补骨脂定(Psoralidin)通过抑制肿瘤坏死因子-α和白细胞介素-6的表达，可抑制骨髓巨噬细胞的破骨细胞生成，致使脂多糖诱导的骨吸收减弱[9]。上述研究结果为补骨脂香豆素类化合物防治OP提供了一定的理论依据。补骨脂香豆素类化合物调控相关信号通路治疗OP的动物实验汇总见表2[7,9-18]。
1.2 黄酮类化合物
目前已从补骨脂中分离出53个黄酮类化合物，其中补骨脂二氢黄酮(Bavachin)、补骨脂二氢黄酮甲醚(Bavachinin)、补骨脂异黄酮(Corylin)、新补骨脂异黄酮(Neobavaisoflavone)具有促进成骨和抑制破骨等多种药理活性，可在抗OP中起重要作用。既往研究发现，新补骨脂异黄酮可上调转录因子Runx2、Osterix mRNA的表达，发挥成骨活性[19]。黄酮类化合物除调节骨代谢外，还可通过其他途径发挥抗OP的作用。Zhu等[20]发现，新补骨脂异黄酮可调节lncRNA CRNDE的表达，保护成骨细胞免受地塞米松引起的氧化应激，从而起到治疗OP的作用。补骨脂黄酮类化合物调控相关信号通路治疗OP的动物实验汇总见表3[20-25]。
1.3 单萜酚类化合物
补骨脂挥发油以单萜酚类为主，目前已分离出单萜酚类化合物23个。最早发现的单萜酚类化合物为补骨脂酚(Bakuchiol)[26]，具有抗肿瘤、抑制细胞增殖、抗氧化、抗菌、抗炎等药理活性。一项关于补骨脂酚治疗去势雄性OP小鼠的研究发现，与模型组相比，治疗组小鼠骨小梁数目及膜下生骨增多，骨小梁间隙减小[27]，表明补骨脂酚可能成为治疗OP的有效化合物。杨胜杰等[28]研究发现，补骨脂酚对OP斑马鱼的骨密度具有明显改善作用，能够促进斑马鱼骨骼钙化正常发育。近年来，关于单萜酚类化合物抗OP性能的报道较少，后续研究应进一步补充及深入探讨补骨脂酚治疗OP的作用机制。补骨脂单萜酚类化合物调控相关信号通路治疗OP的动物实验汇总见表4[21,27-28]。
2 补骨脂活性成分治疗OP的相关信号通路
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2.1 Wnt/β-catenin信号通路
Wnt/β-catenin信号通路在成骨细胞成熟及骨形成中起着重要作用。在缺乏Wnts的情况下，下游目标β-catenin主要由糖原合成激酶3β(glycogen synthase kinase-3β，GSK-3β)磷酸化。Wnt3a与Frizzleed和低密度脂蛋白受体相关蛋白5或6(LRP5/6)共受体结合，一方面诱导β-catenin磷酸化，使细胞质内LRP5/6保持稳定；另一方面GSK-3β受到抑制，导致β-catenin积累，累积的β-catenin转位至细胞核，结合核转录因子T细胞因子/淋巴增强子因子(T cell factor/lymphoid enhancer factor，TCF/LEF)，激活下游相关靶基因，进而促进成骨细胞的分化和增殖[29-30]。若Wnt/β-catenin信号通路被抑制，则成骨细胞增殖分化受到影响，从而引起OP。
Yu等[21]发现，补骨脂异黄酮可诱导GSK-3β磷酸化，促进β-catenin核转位，激活TCF/LEF转录因子，导致β-catenin下游Runx2基因激活，发挥成骨活性。此外研究发现，与假手术组(戊巴比妥钠麻醉后缝合但未切除卵巢)比较，双侧卵巢切除OP模型大鼠Wnt3a、LRP5和下游蛋白β-catenin表达显著降低[22]。补骨脂二氢黄酮与补骨脂酚联用可上调Wnt3a、LRP5、β-catenin的表达，导致细胞表面LRP5积累；游离的LRP5与Wnts和Frizzled结合并激活典型Wnt信号通路，从而促进成骨细胞分化。以上研究结果表明，补骨脂活性成分能够通过激活Wnt/β-catenin信号通路，促进成骨细胞增殖与分化，从而促进骨生长，这为其用于OP治疗提供了理论依据(图1)。
2.2 磷脂酰肌醇-3-激酶(phosphatidylinositol-3-kinase，
PI3K)/蛋白激酶B(protein kinase B，Akt)轴PI3K/Akt作为一种重要的信号通路，可参与调控细胞的存活、生长和分化过程，还可与其他信号转导途径以及转录网络相互作用，在受体酪氨酸激酶激活后，PI3K将磷脂酰肌醇-二磷酸磷酸化，导致磷脂酰肌醇-三磷酸积累并激活Akt，调控下游CyclinD1、胰岛素样生长因子1、Runx2、Bax、Bcl-2等多种蛋白的表达，进而调控成骨细胞的增殖、分化和凋亡过程，对骨骼生长发育起到关键作用[31]。一方面，PI3K/Akt轴下游的GSK-3β诱导β-catenin磷酸化，使得其可被β-Trcp识别，引发β-catenin进行泛素化和蛋白酶体降解；另一方面，通过GSK-3β的磷酸化失活，促使β-catenin积累并激活下游靶基因Runx2和Osterix，进而促进成骨细胞分化[32]。核因子E2相关因子2(nuclear factor erythroid 2 related factor 2，Nrf2)是调控机体氧化应激反应的重要转录因子，可与Kelch样ECH相关蛋白-1(Kelch-like ECH-associated protein 1，Keap1)形成泛素E3连接酶复合物，促进Nrf2降解并控制Nrf2核水平[33-34]。Nrf2/血红素氧合酶-1(HO-1)信号通路位于PI3K/Akt轴下游，作为一种直接清除活性氧(ROS)的主要抗氧化途径，Nrf2不仅能够调节抗氧化活性，而且在调控骨内稳态方面也起着重要作用[35]，由此可见，Nrf2/HO-1信号通路为OP治疗提供了又一条重要的附加途径。
Yin等[10]研究发现，补骨脂素以一种与Keap1无关的方式诱导Nrf2，可显著增高骨骼干细胞的核Nrf2水平，降低胞质中Nrf2水平，表明补骨脂素可能通过促进Nrf2的转位来增强Nrf2介导的抗氧化作用。Zhai等[11]证实，补骨脂定可刺激下游因子GSK-3β而激活PI3K/Akt轴，促进去卵巢OP大鼠的骨形成，并通过增强Nrf-2/HO-1途径及加速ROS的清除，从而有利于骨髓基质细胞的成骨分化和抑制脂肪细胞分化。研究表明，补骨脂定可与雌激素受体(ER)结合，通过与ER信号通路相互作用，促进Nrf2的表达，抑制氧化因子环氧合酶-2(COX-2)的表达和ROS的产生，发挥抗氧化作用并抑制骨丢失[12]。上述研究结果表明，补骨脂活性成分在PI3K/Akt、ER等信号通路中以多种方式激活Nrf2/HO-1信号通路，有效抑制氧化应激，促进成骨细胞分化，抑制骨丢失进而缓解OP(图1)。
2.3 过氧化物酶体增殖物激活受体-γ(peroxisome proliferator-activated receptor-γ，PPAR-γ)/Wnt轴
调控脂肪生成与成骨细胞生成之间平衡的分子机制对于防治OP非常重要，其中，PPAR-γ/Wnt信号通路研究较为广泛。PPAR-γ是一种核激素受体，可抑制成骨细胞特异转录因子的表达，减弱骨形成，促进破骨细胞生成，从而增加骨吸收[36]。Wnt信号通路可诱导骨代谢及骨发育过程中一系列重要调节因子的表达。在PPAR-γ/Wnt信号通路中，Axin2是一个重要的关键调节因子。当Wnt信号被激活时，Axin2表达水平上调，导致Axin2复合物形成，阻止β‑catenin降解。此外，Axin2可与PPAR-γ相互作用，调节其转录活性和下游基因的表达。这种相互作用可能影响脂肪细胞分化、脂质代谢和炎症反应等生理过程[37]。值得注意的是，Wang等[13]研究发现，异补骨脂素灌胃治疗去势OP大鼠，可促进大鼠Wnt/β‑catenin蛋白的表达，抑制PPAR-γ蛋白的表达，因此，异补骨脂素可能通过调节PPAR-γ/Wnt信号通路来治疗OP。此外，王军等[14]指出，异补骨脂素可能通过抑制Axin2/PPAR-γ信号通路，激活Wnt信号通路，从而有效促进OP大鼠成骨细胞增殖和分化以及改善骨代谢异常。
随着氧化应激在OP发病中的作用越来越突出，大量研究发现，老年性OP、绝经性OP及继发性OP都表现出与氧化应激有关。叉头框转录因子O3a(forkhead box transcription factor O3a，FoxO3a)作为叉形头转录因子中O亚型家族之一，参与调控氧化应激、细胞自噬及其他过程；而氧化应激可促进FoxO3a信号通路的激活，导致过量ROS破坏成骨细胞的结构与功能[38]。此外，FoxO3a可上调PPAR-γ的表达水平，激活蛋白酶体降解β-catenin，从而抑制骨髓间充质干细胞向成骨细胞定向分化；同时还可使FoxO与Wnt通路竞争性地结合β-catenin，将细胞内有限的β-catenin导向FoxO转录[39]，抑制成骨细胞增殖及分化，进一步促进OP的发展。有研究对氧化应激介导的OP模型大鼠给予异补骨脂素灌胃治疗14周，发现异补骨脂素可通过抗氧化作用抑制FoxO3a信号通路的激活，同时上调β-catenin蛋白的表达，促进其与FoxO3a结合，启动ROS清除转录程序，促使成骨细胞生成，提示异补骨脂素可能通过调节FoxO3a/Wnt相关信号通路发挥抗OP作用[15]。随着机制研究的不断深入，张宇[16]发现，随着异补骨脂素浓度的增加，其抗OP作用随之增强，同时氧化应激相关指标得到改善，PPAR-γ和Wnt指标也发生变化。由此可见，异补骨脂素可能通过调节PPAR-γ/Wnt信号通路来发挥调节脂质代谢、骨代谢以及抑制氧化应激等作用，从而预防骨质流失和骨质疏松，表明补骨脂活性成分可能成为未来临床上治疗OP的潜在药物(图1)。
2.4 RANKL/RANK/MAPK轴
与成骨细胞不同，破骨细胞在骨吸收过程中具有特殊作用。骨吸收障碍是OP和其他多种骨病发生的根本原因，而调控破骨细胞分化和功能的两个关键因素[核因子-κB受体活化因子配体(receptor activator of nuclear factor-κB ligand，RANKL)与巨噬细胞集落刺激因子(M-CSF)]也发挥着重要作用。M-CSF诱导核因子-κB受体活化因子(receptor activator of nuclear factor-κB，RANK)的表达，而RANKL与破骨细胞表面受体RANK相互作用，进而招募肿瘤坏死因子受体相关蛋白6(tumor necrosis factor receptor-associated factor 6，TRAF6)，进一步激活多种下游信号通路，如三种丝裂原活化蛋白激酶[MAPK，包括p38激酶(p38MAPK)、细胞外信号调节激酶(ERK)和C-Jun N末端激酶(JNK)]等[40-41]。当上述信号分子被激活后，RANK受体中的c-Fos成分可自动增强活化T细胞核因子1(NFATc1)，而c-Fos/NFATc1结合可调控破骨细胞成熟过程中基因的表达，包括组织蛋白酶K和抗酒石酸酸性磷酸酶(tartrate resistant acid phosphatase，TRACP)。MAPK-NFATc1发生于早期破骨细胞生成期间(RANKL刺激后24 h内)，促进构成RANKL的主要下游信号级联；而TRACP和组织蛋白酶K发生于晚期破骨细胞生成期间(RANKL刺激后48 h以上)。这些信号因子均为成熟破骨细胞介导骨吸收过程中的必要因素。
既往研究证实，补骨脂活性成分可通过调控MAPK信号通路来防止骨量流失。Kong等[9]研究发现，补骨脂定可显著抑制RANKL诱导的破骨细胞形成，通过特异性抑制p38、JNK和ERK的激活来抑制RANKL介导的破骨细胞分化。因此，补骨脂定通过抑制RANKL/RANK/MAPK信号通路，展现了其抗破骨细胞生成的潜力。Chai等[17]证实，补骨脂素显著抑制了由M-CSF和RANKL体外诱导小鼠破骨细胞前体细胞中TRACP酶的活性，降低MMP-2和组织蛋白酶K的表达，从而缩小骨陷窝范围及数量，以预防骨质疏松引起的骨吸收。Yuan等[18]发现，给予去势OP小鼠异补骨脂素灌胃后，小鼠TRACP水平降低，骨小梁微观结构改善，骨强度增加，表明异补骨脂素具有治疗性激素缺乏类型OP的潜力。由此可见，针对RANKL/RANK/MAPK信号通路，抑制破骨细胞生成可能是治疗OP更好的策略(图2)。
2.5 核因子-κB(nuclear factor-κB，NF-κB)信号通路
NF-κB信号通路在破骨细胞形成及防治OP中起着至关重要的作用。当RANKL结合并激活RANK受体时，TRAF6和c-Src均被招募，RANK-TRAF6相互作用可激活NF-κB信号通路，从而使核因子κB抑制因子A(recombinant inhibitory subunit of NF kappa B alpha，IκBα)磷酸化并降解，致使核心蛋白p50或p65从细胞质转移到细胞核中，有利于破骨细胞的生成和活化相关因子的转录[42]。
Chen等[23]发现，新补骨脂异黄酮通过阻断RANKL诱导的TRAF6募集，可激活NF-κB信号通路，有效抑制破骨细胞生成以及预防OP大鼠骨丢失。魏晨旭等[24]发现，补骨脂二氢黄酮甲醚对破骨细胞的抑制作用可能与抑制NF-κB信号通路的激活有关。此外，有研究采用Western blotting检测由巨噬细胞克隆刺激因子及RANKL诱导的成熟破骨细胞中IκB、p65、p50的磷酸化水平，证实补骨脂异黄酮能显著抑制RANKL介导的NF-κB通路的激活，从而影响破骨细胞分化[25]。上述研究结果提示，OP可能是因RANKL上调引起破骨细胞增多，因此，抑制机体内过度活化的破骨细胞功能可能是治疗OP的重要途径之一(图2)。
3 总结与展望
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OP与长期饮酒、吸烟、雌激素水平下降、钙和维生素D缺乏、正常衰老，以及某些药物(如皮质类固醇和抗癫痫药)密切相关[43]。OP及其并发症的发病率、致残率和病死率均较高，目前仍是全球主要健康问题，因此加强OP治疗刻不容缓。近年来，从中药中提取的一些活性成分展示出抗骨质流失的作用，且未报告严重不良反应。补骨脂是一种广泛应用的传统中药，其活性成分因具有抗OP作用而受到越来越多的关注，为OP治疗提供了广阔的应用前景。因此，本文综述了近年来关于补骨脂活性成分调控相关信号通路治疗OP领域的研究，以整体角度及多功能层面，探讨了补骨脂活性成分抗OP的分子机制，特别是调节脂质代谢、骨代谢和抗氧化应激信号通路之间的相互关系。结果显示，补骨脂活性成分可通过调节Wnt/β-catenin、PI3K/Akt、PPAR-γ/Wnt、NF-kB、RANKL/RANK/MAPK信号通路的表达水平，调节成骨细胞和破骨细胞的分化或活化，从而参与OP的进程。此外，补骨脂活性成分还可刺激PI3K/Akt轴下游因子GSK-3β，增强Nrf-2/HO-1途径以加速ROS的清除，并与ER信号通路发生特异性相互作用，抑制ROS的产生，达到对氧化应激多层面、多通路的双向调控，最终抑制骨丢失，这种特异性为OP的治疗提供了新的理论依据。
研究表明，氧化应激是由过量的自由基(ROS和活性氮)引起的。这些氧化剂与细胞抗氧化剂防御之间的失衡会导致细胞损伤。超氧化物(O2-)等自由基分子的破坏会引发连锁反应，影响细胞内的DNA、蛋白质、细胞壁脂蛋白和其他结构，起初可能导致单个细胞功能障碍，但随着氧化剂的持续或增加，整个生理系统可能受到影响[44]。氧化应激时，成骨细胞和骨细胞的凋亡率增高[45]。随着骨细胞的死亡，成骨细胞活动的细胞因子减少，从而导致破骨细胞生成进一步增多，而抗氧化剂如谷胱甘肽、N-乙酰-
L-半胱氨酸和α-硫辛酸可减轻这种影响[46]。补骨脂药理作用相关研究多依赖于呋喃香豆素类、黄酮类、单萜酚类三大类化合物，目前已鉴定出96种化合物，但研究多局限于部分成分，且作用机制相关研究较少，限制了其深度开发和应用。因此，未来需借助多学科分析，从分子水平深入探究补骨脂活性成分抗OP的作用，寻找相关信号通路的靶向激动剂或抑制剂，这将有利于多方位探索中医药治疗OP的作用靶点，并验证其科学性，同时，对其安全性的评估也至关重要。基于广泛的研究，补骨脂活性成分在抗氧化应激方面表现突出，并在细胞及动物实验中展现出良好的治疗效果。
综上所述，探讨补骨脂活性成分的抗OP作用及其调控机制，有助于加深对补骨脂药理作用的认识，并为其进一步的药理研究和制剂研发提供参考。补骨脂活性成分有望成为防治OP的新的临床策略，但仍需开展更多临床前研究以评估其作用机制。
基金
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  • 国家自然科学基金(82360937)
  • 广西自然科学基金青年基金(2023GXNSFAA026075)
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2024年第49卷第5期
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doi: 10.11855/j.issn.0577-7402.2279.2023.0620
  • 接收时间：2022-11-03
  • 首发时间：2025-11-21
  • 出版时间：2024-05-28
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出版历史
  • 收稿日期：2022-11-03
  • 录用日期：2023-02-27
基金
National Natural Science Foundation of China(82360937)
国家自然科学基金(82360937)
Guangxi Natural Science Foundation Youth Fund(2023GXNSFAA026075)
广西自然科学基金青年基金(2023GXNSFAA026075)
作者信息
    1广西中医药大学附属瑞康医院骨科，广西南宁 530011
    2广西中医药大学研究生院，广西南宁 530001

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章晓云，E-mail：
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https://castjournals.cast.org.cn/joweb/jfjyxzz/CN/10.11855/j.issn.0577-7402.2279.2023.0620
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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