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Gastrodin,天麻素是一种中药成分，广泛用于治疗血管和神经系统疾病。天麻素在促进组织工程骨愈合方面具有许多独特优势，如在材料表面诱导高亲水性、抗炎作用和促血管再生等。骨质疏松症 a traditional Chinese medicine ingredient, is widely used to treat vascular and neurological diseases. However, recently, an increasing number of studies have shown that gastrodin has anti-osteoporosis effects, and its mechanisms of action include its antioxidant effect, anti-inflammatory effect, and anti-apoptotic effect. In addition, gastrodin has many unique advantages in promoting bone healing in tissue engineering, such as inducing high hydrophilicity in the material surface, its anti-inflammatory effect, and pro-vascular regeneration. (OP) 是一种全身性骨病，其特征是骨量减少、骨组织微结构受损、骨脆性增加和易骨折。天麻素促进骨祖细胞、前成骨细胞和牙周干细胞的活力和成骨分化，抑制破骨细胞分化，从而改善骨形成，减少骨质流失。 Gastrodin promotes the viability and osteogenic differentiation of osteoprogenitor cells, preosteoblasts, and periodontal stem cells, and inhibits osteoclast differentiation, thereby improving bone formation and reducing bone loss.
- gastrodin
- osteoporosis
- bone regeneration
- osseointegration
1. Protection of Osteogenesis
1.保护成骨
1.1. Antioxidant Effect抗氧化作用
Mitochondria线粒体是细胞微环境中的发电厂，为细胞的生存和功能提供动力。骨形成和骨重塑需要大量的能量消耗，而线粒体产生的能量对于维持骨细胞的生长、分化和生物学功能至关重要[ are71 the powerhouses in the cellular microenvironment and provide an impetus for cell survival and function. Bone formation and bone remodeling require significant energy consumption, and the energy produced by the]。对线粒体中氧化磷酸化途径的任何干扰都会损害 mitochondria is essential for maintaining the growth, differentiation, and biological functions of the osteocytes [1]. Any interference with the oxidative phosphorylation pathway in the mitochondria impairs osteogenic gene expression and extracellular matrix (ECM) synthesis in C3H10T1/2 mesenchymal progenitor cells间充质祖细胞中的成骨基因表达和细胞外基质 (ECM) 合成 [2].[ However, oxidative stress can also lead to cellular dysfunction72 ]]. When several 然而，氧化应激也会导致细胞功能障碍。当细胞内产生多种ROS are generated in the cell, they attack the mitochondrial membrane and mitochondrial DNA, which enhances the autophagy of mitochondria and changes the permeability of the outer mitochondrial membrane. These behaviors disrupt the mitochondrial structure and function, resulting in reduced cellular adenosine triphosphate production and increased ROS production, eventually时，它们会攻击线粒体膜和线粒体DNA，从而增强线粒体的自噬作用，改变线粒体外膜的通透性。这些行为破坏了线粒体的结构和功能，导致细胞三磷酸腺苷生成减少和 ROS 生成增加，最终引发线粒体和细胞功能障碍 [ triggering73 mitochondrial and cellular dysfunction [3].]。
The线粒体 mitochondrial ROS balance is achieved by mitochondrial antioxidants, including ROS 平衡是通过线粒体抗氧化剂实现的，包括 Nrf2 [4].[ Gastrodin74 effectively]。天麻素有效清除氧自由基发挥抗氧化活性，下调脂质过氧化水平，抑制解偶联氧化磷酸化，并增加编码抗氧化蛋白（如 scavenges oxygen radicals to exert antioxidant activity, downregulates lipid peroxidation levels, inhibits uncoupled oxidative phosphorylation, and increases the expression of genes encoding antioxidant proteins such as Nrf2 and HO-1Nrf2 和 HO-1）的基因表达 [5][ [6].9 By, upregulating75]. the通过上调 expression of the Nrf2/KEAPl antioxidant pathway (NRF2, HO-1, and1 抗氧化途径（NRF2、HO-1 和 NADPH quinone oxidoreductase-1), gastrodin reduces the dexamethasone-induced oxidative stress levels in 醌氧化还原酶-1）的表达，天麻素降低地塞米松诱导的 MC3T3-E1 cells and mitochondria, increases osteoblast viability, promotes the expression of osteogenesis-related markers such as Runx2, 细胞和线粒体中的氧化应激水平，增加成骨细胞活力，促进表达成骨相关标志物如 Runx2、osterix, bone morphogenetic protein 、骨形态发生蛋白 (BMP) 2, and osteocalcin (OCN), and improves the alkaline phosphatase 和骨钙素 (OCN)，并提高碱性磷酸酶 (ALP) activity and osteogenic mineralization capacity. On the other hand, the antioxidant protective effect of gastrodin is diminished by knocking out 活性和成骨矿化能力。另一方面，天麻素的抗氧化保护作用会因敲除 Nrf2 [7]而减弱 [8].
骨髓间充质干细胞 cells (BMSCs) and osteoblasts和成骨细胞均参与骨形成，前者主要分化为成骨细胞或脂肪细胞 [ are76 involved in bone formation, with the]。体外研究表明，氧化损伤可能通过抑制 former mainly differentiating into osteoblasts or adipocytes [9]. In vitro studies suggest that oxidative damage may partly contribute to OP by inhibiting the osteogenic differentiation of BMSCs [10].的成骨分化而部分促成 InOP elderly[ patients77 with]。在老年 OP, the decrease in BMD is accompanied by a decrease in osteoblasts and increase in adipocytes, suggesting that the balance between osteogenic differentiation and lipogenic differentiation of 患者中，BMD 的降低伴随着成骨细胞的减少和脂肪细胞的增加，提示 BMSCs is one成骨分化和脂肪生成分化之间的平衡是影响骨质量的重要因素之一 [ of78 the, important79 factors affecting bone quality [11] [12]. Gastrodin inhibits ]。天麻素抑制H 2 O 2 -mediated overproduction of ROS in 介导人骨髓基质干细胞（human bone marrow stromal stem cells (hBMMSCs), significantly promotes the proliferation of h）ROS的过量产生，显着促进hBMMSCs, upregulates the expression of the osteogenic genes ALP, BGLAP, and 的增殖，上调成骨基因ALP、BGLAP和COL1A1, protects cellular ALP activity and calcification mineralization, and reduces the expression of the lipogenic genes CFD and LPL. Eventually, gastrodin promotes osteogenic differentiation and inhibits lipogenic differentiation of h的表达，保护细胞ALP活性和钙化矿化，降低脂肪生成基因 CFD 和 LPL。最终，天麻素在氧化应激下促进成骨分化并抑制 hBMMSCs under oxidative的脂肪生成分化 [ stress37 [13].]。
Sirtuin 3 (SIRT3) is a是 protein deacetylase member of the ssirtuin family that is located mainly in the mitochondria. SIRT3 is involved in energy metabolic processes, including the respiratory chain, tricarboxylic acid cycle, fatty acid β-oxidation, and ketogenesis. Thus, 家族的蛋白质脱乙酰酶成员，主要位于线粒体中。SIRT3参与能量代谢过程，包括呼吸链、三羧酸循环、脂肪酸β-氧化和生酮作用。因此，SIRT3 controls the flow of the mitochondrial oxidative pathway and the rate of ROS production控制线粒体氧化途径的流动和 ROS 产生的速率 [14].[ It80 can also]。它还会影响丙二醛 affect malondialdehyde (MDA) levels水平 [15],[ which69 is an important marker of oxidative stress. It has been reported that ]，这是氧化应激的重要标志。据报道，SIRT3-deficient mice present 缺陷小鼠存在 OP [16].[ Human81 periodontal]。人牙周膜干细胞 ligament stem cells (hPDLSCs) can differentiate可以向多个方向分化为牙槽骨和牙周膜样组织 [ into alveolar bone and periodontal ligament-like tissues and in multiple directions [17]82 ]]. In a在脂多糖 lipopolysaccharide (LPS)-induced oxidative damage model of (LPS) 诱导的 hPDLSCs, gastrodin inhibited oxidative stress in hPDLSCs by upregulating SIRT3 gene expression and decreasing the levels of MDA and lactate dehydrogenase, which are markers of oxidative stress. Gastrodin significantly promoted 氧化损伤模型中，天麻素通过上调 SIRT3 基因表达和降低氧化应激标志物 MDA 和乳酸脱氢酶的水平来抑制 hPDLSCs 的氧化应激。天麻素显着促进 hPDLSC’s proliferative viability and ALP activity, mineralized nodules, and increased the expression of the osteogenic differentiation-related proteins ALP, Runx2, OCN, and 的增殖活力和 ALP 活性，矿化结节，并增加成骨分化相关蛋白 ALP、Runx2、OCN 和骨桥蛋白的表达 [ osteopontin69 [15].]。
In在体内，天麻素减少了氧化应激，促进了成骨分化和矿化过程，并增强了糖皮质激素治疗的骨质疏松大鼠的骨微结构和生物力学强度 vivo,[ gastrodin67 reduced]。在 oxidative stress, promoted osteogenic differentiation and mineralization processes, and enhanced bone microstructure and biomechanical strength in glucocorticoid-treated osteoporotic rats [8]. In OVX mice小鼠和 and T2DM rat OP models, gastrodin significantly reduced serum MDA activity, increased glutathione and SOD activity, enhancedT2DM 大鼠 OP 模型中，天麻素显着降低血清 MDA 活性，增加谷胱甘肽和 SOD 活性，增强抗氧化状态，并减轻骨质流失 [ antioxidant37 status, and68 alleviated]。天麻素可降低氟中毒大鼠的血清 bone loss [13] [18]. Gastrodin reduced serum MDA levels,水平，增加 increased SOD activity, reduced ROS accumulation, andSOD 活性，减少 ROS 积累，减轻股骨和牙槽骨损伤 [ alleviated9 femoral and alveolar bone damage in rats with fluorosis [5].]。
1.2. Anti-Apoptotic Effect抗凋亡作用
Apoptosis induction细胞凋亡诱导与细胞凋亡因子如 is closely associated with the release of apoptotic factors such as Bax, cytochrome C, pro-caspases, and apoptosis-inducing factor Bax、细胞色素 C、半胱天冬酶原和细胞凋亡诱导因子 (AIF) [19].的释放密切相关 When[ the83 mitochondria are subjected to stress disorders, ]。当线粒体受到应激障碍时，Bax aggregates and oligomerizes at different sites in the mitochondria and regulates cytochrome C translocation release在线粒体的不同位点聚集和寡聚化并调节细胞色素 C 易位释放 [ [20].84 Cytochrome]。细胞色素 C release initiates caspase-protease-dependent apoptosis. Additionally, AIF can induce chromosomal DNA-independent cell division and enhance apoptosis. However, gastrodin can block this cascade response, reduce the protein expression of Bax, cytochrome C, 释放启动半胱天冬酶蛋白酶依赖性细胞凋亡。此外，AIF 可诱导不依赖于染色体 DNA 的细胞分裂并增强细胞凋亡。然而，天麻素可以阻断这种级联反应，降低 Bax、细胞色素 C、caspase-3 and AIF, and increase the production of the anti-apoptotic factor 和 AIF 的蛋白表达，增加抗凋亡因子 Bcl-2 to inhibit的产生，从而抑制成骨细胞凋亡 [ apoptosis44 in, osteoblasts [7] [8]67 ]]. In a在模拟软骨细胞的体外骨关节炎模型中，天麻素通过抑制核因子 chondrocyte-mimicking in vitro osteoarthritis model, gastrodin attenuated interleukin (IL)-1β-induced chondrocyte apoptosis by inhibiting the nuclear factor kappa kappa B (NF-kB) signaling信号转导减弱白细胞介素 [20]. (ILPS)-1β stimulation significantly诱导的软骨细胞凋亡 [ decreased84 the]。LPS expression of 刺激显着降低 Bcl-2 and increased the expression of Bax, 的表达并增加 Bax、caspase-3, and 和 caspase-9. However, gastrodin pretreatment inhibited the LPS-induced apoptosis of the h 的表达。然而，天麻素预处理抑制了 LPS 诱导的 hPDLSCs [12].
在体内，天麻素降低了氟中毒大鼠的 Bax, 、caspase-3, and 和 caspase-9 protein expression levels and increased 蛋白表达水平，并增加了 Bcl-2 expression in表达 [ rats9 with]。天麻素通过在骨坏死大鼠中发挥抗细胞凋亡作用来降低骨坏死的发生率 fluorosis[ [5].52 Gastrodin reduced the]。它还通过 incidence of osteonecrosis by exerting an anti-apoptotic effect in rats with osteonecrosis [21]. It also improved the peri-implant cancellous bone quality through an anti-apoptotic effect in T2DM rats大鼠的抗细胞凋亡作用改善了种植体周围松质骨的质量 [18].[ Furthermore,68 gastrodin]。此外，天麻素改善了骨关节炎大鼠凋亡因子和抗凋亡因子之间的表达平衡，增加了 improved the balance of expression between apoptotic and anti-apoptotic factors in osteoarthritic rats, increased the deposition of proteoglycans in the ECM, and reducedECM 中蛋白多糖的沉积，减少了对软骨下骨板的损伤 [ damage70 to the subchondral bone plate [22].]。
1.3. Anti-Inflammatory Effect抗炎作用
NF-kB signaling,信号通路是最重要的细胞内信号通路之一，参与炎症和促炎症应激相关反应的调节 one[ of85 the most important intracellular signaling pathways, is involved in the regulation of inflammatory and pro-inflammatory stress-related responses [23]. When stimulated by inflammatory factors, ]。当受到炎症因子的刺激时，NF-kB is被激活以进行核转位并触发炎症相关基因的转录。天麻素减毒 activated to undergo nuclear translocation and trigger the transcription of inflammation-related genes. Gastrodin-attenuated NF-kB nuclear translocation in chondrocytes reduces the ratio of 在软骨细胞中的核转位降低了 p-IkB-α/IkB-α, decreases the expression of the inflammatory factors such as tumor necrosis factor 的比例，降低了肿瘤坏死因子 (TNF)-α and IL-6, reduces the degradation of the ECM and matrix metalloproteinase 3, and和 IL-6 等炎症因子的表达，减少了ECM 和基质金属蛋白酶 3，并维持软骨细胞的细胞内稳态。天麻素改善了体内骨关节炎大鼠模型的软骨退化 [ maintains intracellular homeostasis in the chondrocytes70]. Gastrodin在 improved cartilage degeneration in an osteoarthritis rat model in vivo [22]. In LPS-induced injury of 诱导的 hPDLSCs, gastrodin significantly reduced the expression of 损伤中，天麻素可显着降低 TNF-α and和 IL-6 and alleviated的表达，减轻炎症损伤 [ inflammatory83 injury]。此外，天麻素抑制氧化应激下 [19]. hBMMoreover, gaSCstrodin inhibited the expression of 中 TNF-α and和 IL-6 in hBMMSCs的表达 [ under37 oxidative stress [13], and factors such as receptor activator of ]，NF-kB ligand配体受体激活剂 (RANKL), TNF-α, and、TNF-α 和 IL-6 are highly involved in等因子高度参与雌激素缺乏的 OP 病例 [ estrogen-deficient86 OP cases [24].]。
2. Inhibition of Bone Resorption抑制骨吸收
2.1. Gastrodin Inhibits Osteoclast Differentiation under Oxidative Stress through Antiox-Idant Effect天麻素通过抗氧化作用抑制氧化应激下破骨细胞分化
Osteoclasts are derived from a monocyte破骨细胞来源于单核细胞/macrophage cell line (巨噬细胞细胞系（RAW264.7 cells). They细胞）。它们主要参与骨吸收，能向细胞外分泌盐酸和溶菌酶，破坏和溶解周围的骨组织。成骨细胞和破骨细胞的正常功能是维持骨代谢的稳态 [ are87 mainly involved in bone resorption and can secrete hydrochloric acid and lysozyme extracellularly to destroy and dissolve the surrounding bone tissue. The normal function of osteoblasts and osteoclasts is to maintain the homeostasis of bone metabolism [25]. Substantial evidence suggests that ]。大量证据表明，ROS can可以通过直接促进破骨细胞分化和活性来增加骨吸收 increase[ bone28 resorption]。然而，天麻素可降低氧化应激下 RAW264.7 细胞中的 ROS 水平，抑制 H 2 by directly promoting osteoclast differentiation and activity [26]. However, gastrodin reduces the level of ROS in RAW264.7 cells under oxidative stress, inhibits increased osteoclast-specific gene expression (2诱导的破骨细胞特异性基因表达（NFATc1, 、TRAP, CTR, and CTSK) induced by H 2 O 2 、CTR 和 CTSK）增加, and并减少破骨细胞的数量。因此，天麻素可能通过抑制破骨细胞分化发挥潜在的抗骨质疏松作用 reduces[ the37 number of osteoclasts. Thus, gastrodin may exert potential anti-osteoporotic effects by inhibiting osteoclast differentiation [13].]。
2.2. Gastrodin Inhibits Osteoclast Differentiation in Normal Environment through Antioxidant Effect天麻素通过抗氧化作用抑制正常环境下的破骨细胞分化
Nuclear活化 factor of activated T cellsT 细胞核因子 cl (NFATc1) plays a key role in osteoclast differentiation. 在破骨细胞分化中起关键作用。RANKL activates NFATc1 expression through a series of cascade signals (recruitment of TNF receptor-associated factor 6, mitogen-activated protein kinase, AKT, and通过一系列级联信号（TNF 受体相关因子 6、丝裂原活化蛋白激酶、AKT 和 NF-kB pathway), which leads to the differentiation and maturation of osteoblasts [27]. Exogenous 通路的募集）激活 NFATc1 can表达，从而导致成骨细胞分化和成熟 still[ induce88 osteoclast]。在没有 differentiation in the absence of RANKL, whereasRANKL 的情况下，外源性 NFATc1-deficient embryonic stem cells cannot differentiate into osteoclasts in the presence of 仍然可以诱导破骨细胞分化，而在 RANKL [28]. However, gastrodin effe存在的情况下，NFATctively1 delays the缺陷的胚胎干细胞不能分化为破骨细胞 [ differentiation89 ]]. of the bone marrow-derived macrophages然而，天麻素通过下调 (BMMs) into osteoclasts by downregulating the transcriptional and translational expression of NFATc1. The expression of osteoclast-specific genes, such as TRAP, Cts K, and 的转录和翻译表达，有效地延迟了骨髓来源的巨噬细胞 (BMM) 向破骨细胞的分化。天麻素可显着降低破骨细胞特异性基因（如 TRAP、Cts K 和 DC-STAMP, is）的表达 [ significantly51 reduced by gastrodin [29].]。
Osteoclast破骨细胞分化是一个多步骤的过程，涉及细胞增殖、定型、融合和激活，在融合过程中必须有原破骨细胞的迁移。在伤口愈合实验中，天麻素显着抑制了破骨细胞的迁移。此外，天麻素干预抑制了骨碎片中破骨细胞的骨吸收 differentiation[ is51 a multistep process that involves cell proliferation, commitment, fusion, and activation, and the migration of pro-osteoclasts is necessary during the fusion process. In wound-healing experiments, gastrodin significantly inhibited the migration of pro-osteoclasts. Moreover, the bone resorption by osteoclasts in bone fragments was inhibited by gastrodin intervention [29].]。
In a healthy organism, 在健康机体中，正常水平的ROS at normal levels participate in the regulation of normal operation of various biological functions. The differentiation of osteoclasts requires the activation of RANKL, and this process needs the involvement of moderate ROS参与调节各种生物功能的正常运行。破骨细胞的分化需要RANKL的激活，而这一过程需要中等ROS的参与[ [26].28 Compared with other bone cells,]。与其他骨细胞相比，破骨细胞需要更多的 osteoclasts need more ROS [30].[ Therefore,90 in normal environments, such as this study, gastrodin still inhibits osteoclast differentiation by reducing ]。因此，在正常环境下，如本研究，天麻素仍然通过降低ROS levels. This low level of ROS is insufficient to maintain the activation of RANKL, which is required for osteoclast differentiation.水平来抑制破骨细胞分化。这种低水平的 ROS 不足以维持 RANKL 的激活，而 RANKL 是破骨细胞分化所必需的。
