中医药调控miRNA在股骨头坏死中作用的研究进展
Research Progress on the Role of Traditional Chinese Medicine in Regulating miRNA in Femoral Head Necrosis
DOI: 10.12677/acm.2025.1572008, PDF, HTML, XML,   
作者: 王春蕾*:黑龙江中医药大学第一临床医学院,黑龙江 哈尔滨;李洪涛#:黑龙江中医药大学附属第一医院骨伤一科,黑龙江 哈尔滨
关键词: 股骨头坏死miRNA中医药自噬Osteonecrosis of the Femoral Head miRNA Traditional Chinese Medicine Autophagy
摘要: 股骨头坏死(ONFH)是一种因血液供应不足导致细胞死亡、骨折及区域塌陷的进行性疾病。2023年全球约有3000万患者,我国超812万,约94%的患者5年内会出现股骨头塌陷、行走功能障碍,最终需行人工全髋关节置换术。其病因复杂,与创伤、高脂血症、糖皮质激素使用及酒精等因素相关,发病机制涉及血管内皮损伤、骨细胞凋亡、炎症反应和骨代谢紊乱等。microRNA (miRNA)是一类内源性非编码RNA,通过与靶mRNA的3'-末端非翻译区结合负向调控基因表达,在多种生理过程及骨科疾病发病机制中发挥重要作用。研究ONFH中的miRNA对揭示病理机制、早期诊断及治疗意义重大。本文旨在综合分析文献,探讨中药调控miRNA与ONFH的潜在联系,分析其作为诊断治疗工具的潜力,为读者呈现中医药调控miRNA在ONFH中的重要性的全面视角,推动相关研究和临床应用。
Abstract: Osteonecrosis of the femoral head (ONFH) is a progressive disease caused by insufficient blood supply leading to cell death, fractures, and regional collapse. In 2023, there were approximately 30 million patients worldwide, with over 8.12 million in China. About 94% of patients will experience femoral head collapse and walking dysfunction within five years, eventually requiring total hip arthroplasty. The etiology is complex, related to trauma, hyperlipidemia, glucocorticoid use, and alcohol consumption, among others. The pathogenesis involves vascular endothelial injury, osteocyte apoptosis, inflammatory response, and bone metabolism disorders. MicroRNA (miRNA) is an endogenous non-coding RNA that negatively regulates gene expression by binding to the 3'-untranslated region of target mRNA and plays a significant role in various physiological processes and the pathogenesis of orthopedic diseases. Studying miRNA in ONFH is of great significance for revealing the pathological mechanism, early diagnosis, and treatment. This article aims to comprehensively analyze the literature, explore the potential connection between miRNA regulated by traditional Chinese medicine and ONFH, and analyze its potential as a diagnostic and therapeutic tool, presenting a comprehensive perspective on the importance of traditional Chinese medicine regulating miRNA in ONFH to readers and promoting related research and clinical application.
文章引用:王春蕾, 李洪涛. 中医药调控miRNA在股骨头坏死中作用的研究进展[J]. 临床医学进展, 2025, 15(7): 449-454. https://doi.org/10.12677/acm.2025.1572008

1. 引言

股骨头坏死(ONFH)是一种以股骨头血液供应受阻引发的骨组织逐渐坏死为特征的疾病,具有较高的致残率。目前全球患者数量约有3000万患者,我国超800万,最终约94%的患者在5年需行人工全髋关节置换术[1]。该病发病原因复杂多样,其中创伤、高脂血症、糖皮质激素(GCs)的应用以及长期饮酒等均为常见诱发因素[2]。在发病机制层面,涉及多个细胞类型和分子通路的异常,如血管内皮细胞受损、骨细胞凋亡、炎症反应加剧以及骨代谢失衡等[3]-[5],这使得深入探究其分子机制成为开发有效防治策略的关键[6]。microRNA (miRNA)作为一类重要的内源性非编码RNA分子,在细胞生理过程的调控中发挥着核心作用[7]。其通过与靶mRNA的3'-末端非翻译区特异性结合,实现对靶基因表达的负向调控。已有研究证实,miRNA在生物体的发育、细胞增殖与分化、代谢调控以及细胞外基质形成等众多生理活动中扮演关键角色,尤其在骨骼系统的发育和再生过程中具有不可忽视的作用[8]。此外,miRNA的异常表达还与多种骨科疾病的发病机制密切相关,包括椎间盘退变、骨关节炎、骨质疏松症以及骨肉瘤等[9]。因此,深入研究miRNA在ONFH中的作用,不仅有助于阐明疾病的发病机制,还可能为早期诊断和治疗提供新的靶点和思路。

2. 中药复方调控miRNA在股骨头坏死中的作用

2.1. 对骨细胞分化与代谢的促进作用

miRNA在成骨细胞和破骨细胞分化过程中起着关键的调控作用,进而影响股骨头坏死的进程。成骨细胞主要负责骨组织的形成,而破骨细胞则负责骨组织的吸收,二者之间的动态平衡对于维持骨骼的健康状态具有重要意义[10]。miRNA可通过精准调控特定基因的表达,进而影响骨髓间充质干细胞向成骨细胞的分化过程。例如,miR-135b-5p可能通过上调RUNX2信号通路参与ONFH的发病机制[11]。此外,miRNA-1275p通过抑制磷酸酶和紧张素同源蛋白的表达,间接激活蛋白激酶B,从而促进骨髓间充质干细胞的成骨分化[11]

补肾生骨汤作为国家级老中医王继先临床经验的总结方剂,具有补肾强筋、活血化瘀的功效,在ONFH治疗中取得了显著疗效[12]。相关动物实验研究表明,与对照组相比,ONFH模型组大鼠的股骨头组织出现区域性缺损、骨小梁稀疏等病理改变,血浆中纤维蛋白原(FIB)表达升高,而血管内皮生长因子(VEGF)、一氧化氮合酶(NOS)、骨钙素(BGP)等表达降低。经不同剂量补肾生骨汤干预后,上述病理改变和相关指标异常均得到改善,其中高剂量组效果更为明显[13]。进一步研究发现,ONFH组股骨头组织中miR-135b-5p表达上调,RUNX2表达下调,而补肾生骨汤干预可使miR-135b-5p表达下调,RUNX2表达上调,且联合miR-135b-5p agomir干预会削弱补肾生骨汤的改善作用[13]。这表明补肾生骨汤可能通过下调miR-135b-5p,靶向调控RUNX2,进而促进ONFH大鼠股骨头组织的修复。

祛痰逐瘀方(QZD)由经典方剂四物汤和二陈汤组成,具有多方面的临床药理作用,如在心脑血管疾病治疗方面有一定应用[14]。研究发现,QZD能通过特异性miR-628/Pten/Runx2调控ONFH内骨稳态代谢机制,从而促进坏死组织的修复[15]

2.2. 对骨细胞凋亡的影响

内质网(ER)是真核细胞内重要的膜结合细胞器,在蛋白质和脂质合成等过程中发挥关键作用[16]。细胞凋亡作为一种程序性细胞死亡事件,对于维持组织稳态、生物体生长发育等具有重要意义,但其异常调节与多种疾病的发生发展密切相关。当内质网受到损伤时,细胞会启动未折叠蛋白反应以减轻内质网应激,然而长期、严重的内质网应激可导致细胞凋亡[17] [18]。在ONFH中,内质网应激与成骨细胞凋亡增加、成骨细胞发育减少、破骨细胞凋亡以及骨重塑紊乱等典型症状相关[19]

袁氏生脉成骨片是广州中医药大学附属第一医院自制的中成药,具有活血化瘀、补肾健骨、补益肝肾、通脉止痛等功效,可促进ONFH成骨与周围毛细血管形成,改善股骨头血运,缓解疼痛引起的肌肉紧张,增强骨质强度,促进股骨头修复[20]。一项实验研究表明,将第三代成骨细胞分为不同组别,通过提取总RNA并进行质检,找出不同组间的差异表达miRNA并分析其表达谱。结果表明,与空白组相比,激素组中有4个miRNA表达上调,2个miRNA表达下调;与空白组相比,中药组中有19个miRNA表达上调,44个miRNA表达下调;与激素组相比,中药组中有11个miRNA表达上调,45个miRNA表达下调。其中,miR-672-5p在激素组与空白组对照中上调,而在中药组与激素组对照中相对应下降,提示袁氏生脉成骨片治疗股骨头坏死的机理是在激素作用下miR-672-5p上调,调控靶基因抑制血管生成和增加脂肪细胞,破坏骨细胞的平衡,诱导股骨头坏死的发生,而袁氏生脉成骨片抑制了miR-672-5p的上调,从而保护骨细胞平衡,抑制股骨头坏死的发生[21]

3. 中药单体调控miRNA在股骨头坏死中的作用

3.1. 自噬调控作用

自噬是一种广泛存在于细胞中的自我降解过程,对于维持细胞内环境稳态具有重要意义[22]。近年来,自噬在人类健康和疾病中的重要作用得到了重视,自噬在各种应激条件下的保护作用也得到了证实[23]。在骨代谢方面,自噬对成骨细胞分化、成熟骨形成维持等方面具有重要影响例如。Liu等[24]人发现,自噬在成骨细胞分化过程中被激活。此外,Zhang等[25]报道了多种自噬相关基因的表达与骨密度相关。自噬对成熟骨形成的维持具有重要意义,是成骨细胞重要的保护机制[26]

淫羊藿作为常用补肾壮骨中药,其主要活性成分淫羊藿苷(ICA)近年来受到广泛关注[27]。ICA具有调控骨髓间充质干细胞、促进成骨细胞分化、抑制破骨细胞功能等多种药理作用,其作用机制涉及多个信号通路,如Wnt/β-catenin、BMP-2/RunX2/OSX等,同时对PPARγ等成脂分化相关因子具有抑制作用[28]。此外,ICA还具有免疫调节和抗炎作用,可减轻骨组织炎症反应,保护骨质。研究表明,ICA能显著抑制低浓度激素诱导的股骨头骨髓间充质干细胞来源的骨微血管内皮细胞(BMECs)自噬,增加外泌体中VEGFA和TGF-β1等蛋白的表达水平,从而促进内皮细胞迁移和血管生成[29]

3.2. 对骨髓间充质干细胞增殖的促进作用

骨髓间充质干细胞具有自我更新和多向分化潜能,在骨形成过程中发挥着关键作用[30]。ONFH的发生与股骨近端骨髓间充质干细胞的改变存在关联[31]。糖皮质激素(GCs)可诱导骨髓间充质干细胞氧化损伤,抑制其增殖和成骨分化,进而导致骨坏死[32]。近年来,基于骨髓间充质干细胞的治疗方法受到研究者们的关注。体内外研究表明,移植的间充质干细胞(MSCs)可分化为成骨细胞,促进骨矿化,显示出在骨坏死治疗中的潜力[33]

鹿角作为一种传统的保健食品和药品,在中国、日本和韩国已有数千年的应用历史[34]。现代研究发现,鹿角中富含多种生物活性化合物,如肽、脂质、多糖等,具有强化骨骼、治疗神经紊乱等多种药理作用[35]。最近多项实验研究表明,激素可引起miR-141表达增加,而鹿茸血清能够有效抑制由激素引起的miR-141高表达,从而促进骨髓间充质干细胞增殖活性,减弱激素对骨髓间充质干细胞抑制成骨的作用[36] [37]

3.3. 对铁死亡的调控作用

铁死亡是一种新发现的铁介导的细胞死亡形式,其特征是脂质过氧化产物和活性氧水平升高[38]。铁死亡与多种病理过程相关,如炎症相关疾病、神经退行性疾病、癌症等。研究发现,地塞米松在糖皮质激素致股骨头骨坏死中可通过P53/SLC7A11/GPX4通路诱导铁死亡[39]。三七作为五加科多年生草本植物,其根部具有化瘀止血、活血定痛等功效,三七总皂苷是其主要有效成分之一,具有改善微循环、增加血流量等作用[40]。研究显示,三七总皂苷可抑制破骨细胞分化,促进破骨细胞凋亡[41]。通过对破骨细胞来源外泌体进行miRNA测序及生信分析,发现相关miRNA主要富集在细胞周期、细胞分裂、细胞增殖正调控以及与铁死亡相关的PI3K-Akt信号通路、p53信号通路等,表明细胞分化以及成骨细胞铁死亡可能对激素性股骨头坏死的发生发展过程具有重要作用[42]。此外,研究表明破骨细胞来源外泌体中的miRNA可通过介导成骨细胞铁死亡相关基因诱发激素性股骨头坏死[43] [44]

4. 讨论

中医药调控miRNA在股骨头坏死治疗中展现出独特优势,涉及促进骨细胞分化与代谢、调控骨细胞凋亡、自噬、骨髓间充质干细胞增殖以及铁死亡等多个方面。补肾生骨汤可通过下调miR-135b-5p靶向调控RUNX2,促进股骨头组织修复;祛痰逐瘀方经miR-628/Pten/Runx2调控骨稳态代谢机制,促进坏死修复;袁氏生脉成骨片可能通过调控miR-672-5p影响血管生成和脂肪细胞生成,进而破坏骨细胞平衡,诱导股骨头坏死的发生。在中药单体方面,淫羊藿苷可抑制激素诱导的骨微血管内皮细胞自噬,增加外泌体中相关蛋白表达,促进血管生成;鹿茸血清可抑制激素引起的miR-141高表达,促进骨髓间充质干细胞增殖;三七总皂苷可能通过调控破骨细胞外泌体来源miRNA的表达调节成骨细胞铁死亡。

综上所述,深入研究中医药调控miRNA的具体通路及靶点,将为股骨头坏死的治疗提供新的思路和依据,有望推动该领域的发展,为患者带来更多的治疗选择和希望。

NOTES

*第一作者。

#通讯作者。

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