用于治疗骨质疏松症的天麻素

用于治疗骨质疏松症的天麻素: Comparison

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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Gastrodin, 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 (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。regeneration. 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.保护成骨

1. Protection of Osteogenesis

1.1. 抗氧化作用Antioxidant Effect

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Mitochondria are 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 mitochondria is essential for maintaining the growth, differentiation, and biological functions of the osteocytes [ 71 ]. ]。对线粒体中氧化磷酸化途径的任何干扰都会损害Any interference with the oxidative phosphorylation pathway in the mitochondria impairs osteogenic gene expression and extracellular matrix (ECM) synthesis in C3H10T1/2 间充质祖细胞中的成骨基因表达和细胞外基质 (ECM) 合成mesenchymal progenitor cells [ 72 ]]. 然而，氧化应激也会导致细胞功能障碍。当细胞内产生多种However, oxidative stress can also lead to cellular dysfunction. When several ROS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 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 triggering mitochondrial and cellular dysfunction [ 73 ]。.

线粒体The mitochondrial ROS 平衡是通过线粒体抗氧化剂实现的，包括balance is achieved by mitochondrial antioxidants, including Nrf2 [ 74 ]. ]。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Gastrodin effectively 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 和 HO-1）的基因表达and HO-1 [ 9 , 75 ]. By 通过上调upregulating the expression of the Nrf2/KEAP1 抗氧化途径（NRF2、HO-1 和l antioxidant pathway (NRF2, HO-1, and NADPH 醌氧化还原酶-1）的表达，天麻素降低地塞米松诱导的quinone oxidoreductase-1), gastrodin reduces the dexamethasone-induced oxidative stress levels in MC3T3-E1 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cells and mitochondria, increases osteoblast viability, promotes the expression of osteogenesis-related markers such as Runx2、, osterix、骨形态发生蛋白, bone morphogenetic protein (BMP) 2 和骨钙素, and osteocalcin (OCN)，并提高碱性磷酸酶, and improves the alkaline phosphatase (ALP) 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 而减弱activity and osteogenic mineralization capacity. On the other hand, the antioxidant protective effect of gastrodin is diminished by knocking out Nrf2 [ 44 , 67 ]。.

骨髓间充质干细胞Both bone marrow-derived mesenchymal stem cells (BMSCs) 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 and osteoblasts are involved in bone formation, with the former mainly differentiating into osteoblasts or adipocytes [ 76 ]. ]。体外研究表明，氧化损伤可能通过抑制In vitro studies suggest that oxidative damage may partly contribute to OP by inhibiting the osteogenic differentiation of BMSC 的成骨分化而部分促成 OP s [ 77 ]. In ]。在老年elderly patients with OP 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, 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 BMSCs 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 is one of the important factors affecting bone quality [ 78 , 79 ]. ]。天麻素抑制Gastrodin inhibits H ₂O ₂-介导人骨髓基质干细胞（mediated overproduction of ROS in human bone marrow stromal stem cells (hBMMSCs）ROS的过量产生，显着促进s), significantly promotes the proliferation of hBMMSCs的增殖，上调成骨基因ALP、BGLAP和, upregulates the expression of the osteogenic genes ALP, BGLAP, and COL1A1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, 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 hBMMSCs 的脂肪生成分化under oxidative stress [ 37 ]。.

Sirtuin 3 (SIRT3) 是is a protein deacetylase member of the sirtuin 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 控制线粒体氧化途径的流动和 ROS 产生的速率 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, SIRT3 controls the flow of the mitochondrial oxidative pathway and the rate of ROS production [ 80 ]. ]。它还会影响丙二醛It can also affect malondialdehyde (MDA) 水平levels [ 69 ], ]，这是氧化应激的重要标志。据报道，which is an important marker of oxidative stress. It has been reported that SIRT3 缺陷小鼠存在-deficient mice present OP [ 81 ]. Human ]。人牙周膜干细胞periodontal ligament stem cells (hPDLSCs) 可以向多个方向分化为牙槽骨和牙周膜样组织 can differentiate into alveolar bone and periodontal ligament-like tissues and in multiple directions [ 82 ]]. In a 在脂多糖lipopolysaccharide (LPS) 诱导的-induced oxidative damage model of hPDLSCs, gastrodin inhibited oxidative stress in hPDLSCs 氧化损伤模型中，天麻素通过上调by upregulating 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 gene expression and decreasing the levels of MDA and lactate dehydrogenase, which are markers of oxidative stress. Gastrodin significantly promoted hPDLSC 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’s proliferative viability and ALP activity, mineralized nodules, and increased the expression of the osteogenic differentiation-related proteins ALP, Runx2, OCN, and osteopontin [ 69 ]。.

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In vivo, gastrodin reduced oxidative stress, promoted osteogenic differentiation and mineralization processes, and enhanced bone microstructure and biomechanical strength in glucocorticoid-treated osteoporotic rats [ 67 ]. ]。在In OVX 小鼠和mice and T2DM 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rat OP models, gastrodin significantly reduced serum MDA activity, increased glutathione and SOD activity, enhanced antioxidant status, and alleviated bone loss [ 37 , 68 ]. ]。天麻素可降低氟中毒大鼠的血清Gastrodin reduced serum MDA 水平，增加 SOD 活性，减少 ROS 积累，减轻股骨和牙槽骨损伤levels, increased SOD activity, reduced ROS accumulation, and alleviated femoral and alveolar bone damage in rats with fluorosis [ 9 ]。.

1.2. 抗凋亡作用Anti-Apoptotic Effect

细胞凋亡诱导与细胞凋亡因子如Apoptosis induction is closely associated with the release of apoptotic factors such as Bax、细胞色素 C、半胱天冬酶原和细胞凋亡诱导因子, cytochrome C, pro-caspases, and apoptosis-inducing factor (AIF) 的释放密切相关 [ 83 ]. ]。当线粒体受到应激障碍时，When the mitochondria are subjected to stress disorders, Bax 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aggregates and oligomerizes at different sites in the mitochondria and regulates cytochrome C translocation release [ 84 ]. ]。细胞色素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、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, caspase-3 和 AIF 的蛋白表达，增加抗凋亡因子and AIF, and increase the production of the anti-apoptotic factor Bcl-2 的产生，从而抑制成骨细胞凋亡to inhibit apoptosis in osteoblasts [ 44 , 67 ]]. 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In a chondrocyte-mimicking in vitro osteoarthritis model, gastrodin attenuated interleukin (IL)-1β-induced chondrocyte apoptosis by inhibiting the nuclear factor kappa B (NF-kB) 信号转导减弱白细胞介素 (IL)-1β 诱导的软骨细胞凋亡 signaling [ 84 ]. ]。LPS 刺激显着降低stimulation significantly decreased the expression of Bcl-2 的表达并增加 Bax、 and increased the expression of Bax, caspase-3 和, and caspase-9 的表达。然而，天麻素预处理抑制了 LPS 诱导的. However, gastrodin pretreatment inhibited the LPS-induced apoptosis of the hPDLSCs 凋亡 [ 79 ]。.

在体内，天麻素降低了氟中毒大鼠的In vivo, gastrodin reduced Bax、, caspase-3 和, and caspase-9 蛋白表达水平，并增加了protein expression levels and increased Bcl-2 表达expression in rats with fluorosis [ 9 ]. ]。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Gastrodin reduced the incidence of osteonecrosis by exerting an anti-apoptotic effect in rats with osteonecrosis [ 52 ]. ]。它还通过It also improved the peri-implant cancellous bone quality through an anti-apoptotic effect in T2DM 大鼠的抗细胞凋亡作用改善了种植体周围松质骨的质量rats [ 68 ]. ]。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Furthermore, gastrodin improved the balance of expression between apoptotic and anti-apoptotic factors in osteoarthritic rats, increased the deposition of proteoglycans in the ECM 中蛋白多糖的沉积，减少了对软骨下骨板的损伤, and reduced damage to the subchondral bone plate [ 70 ]。.

1.3. 抗炎作用Anti-Inflammatory Effect

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 of the most important intracellular signaling pathways, is involved in the regulation of inflammatory and pro-inflammatory stress-related responses [ 85 ]. ]。当受到炎症因子的刺激时，When stimulated by inflammatory factors, NF-kB 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is activated to undergo nuclear translocation and trigger the transcription of inflammation-related genes. Gastrodin-attenuated NF-kB 在软骨细胞中的核转位降低了 nuclear translocation in chondrocytes reduces the ratio of p-IkB-α/IkB-α 的比例，降低了肿瘤坏死因子, decreases the expression of the inflammatory factors such as tumor necrosis factor (TNF)-α 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and IL-6, reduces the degradation of the ECM and matrix metalloproteinase 3, and maintains intracellular homeostasis in the chondrocytes. Gastrodin improved cartilage degeneration in an osteoarthritis rat model in vivo [ 70 ]. 在In LPS 诱导的-induced injury of hPDLSCs 损伤中，天麻素可显着降低, gastrodin significantly reduced the expression of TNF-α 和and IL-6 的表达，减轻炎症损伤and alleviated inflammatory injury [ 83 ]. ]。此外，天麻素抑制氧化应激下Moreover, gastrodin inhibited hBMMSCs 中the expression of TNF-α 和and IL-6 的表达in hBMMSCs under oxidative stress [ 37 ], ]，and factors such as receptor activator of NF-kB 配体受体激活剂ligand (RANKL)、TNF-α 和 IL-6 等因子高度参与雌激素缺乏的 OP 病例, TNF-α, and IL-6 are highly involved in estrogen-deficient OP cases [ 86 ]。.

2. 抑制骨吸收Inhibition of Bone Resorption

2.1. 天麻素通过抗氧化作用抑制氧化应激下破骨细胞分化Gastrodin Inhibits Osteoclast Differentiation under Oxidative Stress through Antiox-Idant Effect

破骨细胞来源于单核细胞Osteoclasts are derived from a monocyte/巨噬细胞细胞系（macrophage cell line (RAW264.7 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cells). They are 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 [ 87 ]. ]。大量证据表明，Substantial evidence suggests that ROS 可以通过直接促进破骨细胞分化和活性来增加骨吸收 can increase bone resorption by directly promoting osteoclast differentiation and activity [ 28 ]. ]。_{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}However, gastrodin reduces the level of ROS ₂诱导的破骨细胞特异性基因表达（in RAW264.7 cells under oxidative stress, inhibits increased osteoclast-specific gene expression (NFATc1、, TRAP、CTR 和 CTSK）增加, CTR, and CTSK) induced by H ₂O ₂, and reduces the number of osteoclasts. Thus, gastrodin may 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exert potential anti-osteoporotic effects by inhibiting osteoclast differentiation [ 37 ]。.

2.2. Gastrodin Inhibits Osteoclast Differentiation in Normal Environment through Antioxidant 天麻素通过抗氧化作用抑制正常环境下的破骨细胞分化Effect

活化Nuclear factor of activated T 细胞核因子cells cl (NFATc1) 在破骨细胞分化中起关键作用。plays a key role in osteoclast differentiation. RANKL 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activates NFATc1 expression through a series of cascade signals (recruitment of TNF receptor-associated factor 6, mitogen-activated protein kinase, AKT, and NF-kB 通路的募集）激活pathway), which leads to the differentiation and maturation of osteoblasts [ 88 ]. Exogenous NFATc1 表达，从而导致成骨细胞分化和成熟can still induce osteoclast differentiation in [the 88absence ]。在没有of RANKL 的情况下，外源性, whereas NFATc1 仍然可以诱导破骨细胞分化，而在-deficient embryonic stem cells cannot differentiate into osteoclasts in the presence of RANKL 存在的情况下，NFATc1 缺陷的胚胎干细胞不能分化为破骨细胞 [ 89 ]]. However, gastrodin effectively 然而，天麻素通过下调delays the differentiation of the bone marrow-derived macrophages (BMMs) into osteoclasts by downregulating the transcriptional and translational expression of NFATc1 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. The expression of osteoclast-specific genes, such as TRAP, Cts K, and DC-STAMP）的表达, is significantly reduced by gastrodin [ 51 ]。.

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Osteoclast differentiation is 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 [ 51 ]。.

在健康机体中，正常水平的In a healthy organism, 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 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 [ 28 ]. ]。与其他骨细胞相比，破骨细胞需要更多的Compared with other bone cells, osteoclasts need more ROS [ 90 ]. ]。因此，在正常环境下，如本研究，天麻素仍然通过降低Therefore, we speculate that in normal environments, such as this study, gastrodin still inhibits osteoclast differentiation by reducing ROS水平来抑制破骨细胞分化。这种低水平的 ROS 不足以维持 levels. This low level of ROS is insufficient to maintain the activation of RANKL 的激活，而 RANKL 是破骨细胞分化所必需的。, which is required for osteoclast differentiation.