骨质疏松症的诊治及应用间充质干细胞的治疗现状

骨质疏松症是一种系统性的代谢性骨骼疾病, 其特征是骨量减少和骨微结构退化, 导致骨骼脆性和骨折风险的增加。在成人中, 骨髓间充质干细胞在骨骼中主要分化为成骨细胞和脂肪细胞, 当其分化失衡, 分化的脂肪细胞增多, 成骨细胞减少, 最终会演变成骨质疏松症。骨质疏松症越来越被认为是一个主要的公共健康问题, 对全世界超过2亿人有影响, 每年造成超过890万的骨折, 其中以髋骨骨折为主。随着人口老龄化的加剧, 花费在骨质疏松症的个人和社会成本逐年增加, 这对公共卫生保健体系提出了挑战。因此, 早期预防和诊断骨质疏松症的重要性不言而喻。此外, 由于间充质干细胞有成骨潜能, 且被发现可用于骨骼的修复和维护, 自体、异体或转基因骨髓间充质干细胞移植可有效增加骨量和骨密度, 增加骨机械强度, 纠正骨代谢失衡, 其有望成为骨质疏松症治疗的新策略和方法。本文将围绕骨质疏松症的诊断、治疗和间充质干细胞的应用现状展开如下综述。     

雌三醇在治疗骨质疏松症中的作用机制研究

骨质疏松症是以骨量减少、骨的微观结构改变,致使骨的脆性增加,以致易于发生骨折的一种全身代谢性骨骼疾病。本实验通过对培养的成骨细胞添加特定浓度的雌三醇,观察其对成骨细胞增值和分化的影响。为临床应用雌激素治疗骨质疏松症提供了一定的客观依据。     

miR-146a对慢性骨病骨相关细胞增殖、分化、凋亡调控机制的研究现状

在人体骨骼中,间充质干细胞、成骨细胞、破骨细胞和软骨细胞等细胞共同参与骨代谢,调控异常会导致骨质疏松症、骨关节炎等慢性骨病。研究发现,微小RNA可以调控间充质干细胞、成骨细胞、破骨细胞和软骨细胞等细胞的增殖、分化和凋亡等多种生理病理过程,是调控骨质疏松症、骨关节炎等慢性骨病骨代谢的关键因子。本文着重综述并探讨了微小RNA 146a对间充质干细胞、成骨细胞、破骨细胞和软骨细胞的调控机制,以期为骨质疏松症、骨关节炎等慢性骨病的防治药物的研发与应用提供参考。     

葛根素防治骨质疏松症的作用机制研究进展

我国骨质疏松症的患病率高,是老年患者致残和致死的主要原因之一。葛根素是葛根中主要活性成分,可促进成骨细胞的增殖分化、抑制骨吸收和破骨细胞的分化形成、促进骨髓间充质干细胞向成骨分化、发挥雌激素样作用。综述了葛根素防治骨质疏松症的作用机制研究进展,为深入开展葛根素治疗骨质疏松症的基础研究和新药开发提供参考。     

骨形态发生蛋白介导的Smad依赖途径和Smad非依赖途径对骨质疏松症的潜在调节作用研究进展

糖皮质激素长期使用、雌激素减少、继发性甲状旁腺功能亢进、骨组织微环境改变等多种因素均可诱发骨质疏松症。骨代谢失衡(成骨-成脂失衡)是骨质疏松症发病的关键机制,而骨髓间充质干细胞分化为脂肪细胞增加和成骨细胞减少是导致骨质疏松症成骨-成脂失衡的核心。骨形态发生蛋白(bone morphogenesis protein,BMP)则是调控骨质疏松症成骨-成脂平衡的关键蛋白,而这一调控作用又是通过Smad依赖途径和Smad非依赖途径来实现的。本文重点介绍了BMP介导的Smad依赖途径和Smad非依赖途径,并详细介绍了BMP-2、BMP-4、BMP-6、BMP-7、BMP-9通过上述途径参与骨质疏松症成骨、成脂代谢调控的可能机制,以期为临床抗骨质疏松症药物有效靶点的筛选提供新思路。     

中药单体及复方干预Wnt信号通路调控骨代谢的研究进展

骨代谢是指骨骼重塑过程中发生的分解合成代谢,其平衡由骨吸收和骨形成调控。这种平衡稍有偏差就会导致各种骨骼疾病,如骨质疏松症、肾性骨病等。中药单体和复方在治疗骨代谢疾病方面具有一定优势。Wnt信号通路包括依赖β-连环蛋白（β-catenin）的经典Wnt信号通路和不依赖β-catenin的非经典Wnt信号通路,且2种通路均可通过调控骨形成和骨吸收来维持骨代谢平衡,对骨骼发育、骨量维持和骨重塑至关重要。近年来,多种中药单体（如芍药内酯苷、梓醇、淫羊藿苷）以及中药复方（如左归丸、益肾固骨方、杜仲健骨方等）被证实可通过激活Wnt信号通路,促进骨髓间充质干细胞成骨分化、成骨细胞增殖和分化来修复骨损伤和治疗骨质疏松症。基于此,本文总结了中药单体及复方干预Wnt信号通路调控骨代谢的研究进展,以期为中药防治骨代谢疾病的临床应用及新药研发提供思路。     

中药调节PMOP成骨与成脂分化平衡的研究进展

绝经后骨质疏松症发病风险逐年上升,其发病与骨平衡的破坏有关,成骨细胞功能衰减、骨形成不足,最终导致净骨量丢失。而骨形成又与骨髓间充质干细胞(Bone marrow mesenchymal stem cells,BMSCs)的成骨分化和成脂分化关系密切,其分化受多条信号通路调控。本文主要对中药调控骨髓间充质干细胞的分化及其机制进行总结与分析。     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

SEMA3A有助于骨稳态平衡

骨骼疾病如骨质疏松症是由于骨吸收（破骨细胞介导）和骨形成（成骨细胞介导）的自然过程之间的失衡所致。目前多数药物旨在减少骨的再吸收率以纠正这种不平衡,但破骨细胞和成骨细胞活性之间的关联被破坏,也可能引起新骨形成的减少。     

他汀类药物对骨代谢影响的研究进展

他汀类药物作为降低胆目醇的主要药物,具有稳定动脉斑块、抗炎和抗氧化作用,临床应用广泛。近年来,许多基础及临床研究表明,他汀类药物可通过抑制甲羟戊酸途径,促进骨形态发生蛋白-2基因表达;阻止脂肪细胞生成,同时使骨髓基质干细胞向成骨细胞分化;调节核因子（NF）-κB通路,抑制NF—κB受体激活剂所诱导的破骨细胞形成等多种作用机制影响骨代谢,从而使他汀类药物成为骨质疏松症药物治疗的研究热点。     

Controlling the balance between osteoblastogenesis and adipogenesis and the consequent therapeutic implications

The increase in marrow adipogenesis associated with osteoporosis and age-related osteopenia is well known clinically. However, we are only now beginning to understand the mechanisms that control the differentiation of mesenchymal stem cells to either osteoblasts or adipocytes. Recent work with gene silencing and overexpression has provided insight into critical pathways that determine the fate of these multipotential cells. One of these pathways - that of the nuclear hormone receptor peroxisome proliferator activated receptor-gamma - when activated, promotes adipogenesis and inhibits osteogenesis. This in vitro mechanism of action has been confirmed in vivo using ligands to this receptor. Discovery of this and other targets and pathways, such as Wnt signaling, notch/delta/jagged ligands and receptors, and RhoA gene expression, provides new insights into mesenchymal stem cell differentiation. These pathways provide exciting future pharmacological targets with which to enhance bone formation and therefore reduce the risk of fracture.     

槲皮素改善骨质疏松的作用机制研究进展

骨质疏松症是目前老龄化社会急需解决的慢性骨科疾病，是一种以骨量丧失、骨微结构恶化为特征的全身性骨骼疾病，因此如何有效地预防和治疗骨质疏松症越来越受到人们的关注。槲皮素是自然界广泛存在天然黄酮醇类化合物，具有雌激素样作用，可抑制骨吸收和促进骨形成。槲皮素通过抑制破骨细胞、调控骨髓间充质干细胞的细胞机制，促进骨形成、抑制骨吸收的信号通路机制，以及雌激素信号途径改善骨质疏松。综述了槲皮素改善骨质疏松的作用机制，希望为槲皮素的临床应用提供参考。     

过氧化物酶体增殖物激活受体γ及其激动剂噻唑烷二酮类药物对骨骼成骨的影响及作用机制

过氧化物酶体增殖物激活受体γ(PPARγ)及配体是影响骨髓间充质干细胞分化与成熟的重要调控因子,可通过降低骨钙素、骨形成蛋白2等成骨细胞特异性成熟因子的表达,抑制成骨细胞的分化,亦可诱导成骨细胞的凋亡,最终导致骨丢失。目前普遍认为PPARγ参与了老年性骨质疏松、绝经后骨质疏松和继发性骨质疏松的发生、发展。PPARγ激动剂噻唑烷二酮类药物(TZDs)因其导致骨量降低、增加骨折发生率而备受争议,通过化学结构修饰将有可能避免这一不良反应发生。     

骨质疏松hub基因筛选验证及互作miRNA预测

目的 筛选老年性骨质疏松症hub基因及其互作的miRNA。方法 从GEO数据库下载GSE35956基因芯片数据集,利用R语言筛选骨质疏松症患者骨髓间充质干细胞中的差异表达基因（Degs）。利用DAVID数据库对Degs进行GO富集和KEGG通路分析。采用String数据库和Cytoscape软件分析蛋白互作网络,筛选hub基因。通过Targetscan数据库预测与hub基因存在互作关系的miRNA,并通过funrich数据库对预测出的miRNA进行富集分析。提取并培养3～4月龄（青年组）和18～20月龄（老年组）C57BL/6小鼠的骨髓间充质干细胞,采用荧光定量PCR(qPCR)验证2组小鼠的骨髓间充质干细胞中hub基因表达情况。结果 骨质疏松症患者骨髓间充质干细胞中共鉴定出982个上调的Degs和99个下调的Degs。Degs主要富集到质膜黏附分子介导的同型细胞黏附和钙离子结合等生物过程,主要参与了神经活性配体-受体相互作用信号通路。PPI互作网络分析筛选出8个核心基因：瘦素（LEP）、淋巴细胞特异性蛋白酪氨酸激酶（LCK）、WT1转录因子（WT1）、SRY-Box转录因子10(SO...     

Bone marrow niches for hematopoietic stem cells and immune cells

In mammals, hematopoietic stem cells (HSCs), which give rise to all blood cells and their progenies, including immune cells are controlled by special microenvironments, termed niches in the bone marrow during homeostasis and infection. However, the identity, nature and function of these niches remain unclear. It has been reported that HSCs are in contact with osteoblasts lining the bone surface and osteoblasts act as niches for HSCs (termed endosteal niche). However, recent studies suggest that only a small number of HSCs reside in the endosteal niche. In contrast, many HSCs are shown to be in contact with endothelial cells in the marrow. In addition, recent studies suggest that primitive mesenchymal cells, including CXCL12-abundant reticular (CAR) cells and Nestin-expressing cells, which have the ability to differentiate into adipocytes as well as osteoblasts act as niches for HSCs. Here we review candidate niches for HSCs in the bone marrow controlling hematopoiesis and chronic inflammation.     

Hepatocyte growth factor and alternative splice variants - expression,regulation and implications in osteogenesis and bone health and repair

Introduction: Bone marrow-derived mesenchymal stem cells (MSCs) can differentiate into multiple cell types, including osteoblasts, chondrocytes, and adipocytes. These pluripotent cells secrete hepatocyte growth factor (HGF), which regulates cell growth, survival, motility, migration, mitogenesis and is important for tissue development/regeneration. HGF has four splice variants, NK1, NK2, NK3, and NK4 which have varying functions and affinities for the HGF receptor, cMET. HGF promotes osteoblastic differentiation of MSCs into bone forming cells, playing a role in bone development, health and repair.

Areas Covered: This review will focus on the effects of HGF in osteogenesis, bone repair and bone health, including structural and functional insights into the role of HGF in the body.

Expert Opinion: Approximately 6.2 million Americans experience a fracture annually, with 5-10% being mal- or non-union fractures. HGF is important in priming MSCs for osteogenic differentiation in vitro and is currently being studied to assess its role during bone repair in vivo. Due to the high turnover rate of systemic HGF, non-classic modes of HGF-treatment, including naked-plasmid HGF delivery and the use of HGF splice variants (NK1 & NK2) are being studied to find safe and efficacious treatments for bone disorders, such as mal- or non-union fractures.