运动介导microRNAs调控骨代谢的研究进展

运动改善骨代谢,促进骨骼生长发育,缓解骨量流失的作用已被广泛证实。在骨代谢中,微小RNA(microRNAs,miRNAs)广泛参与骨髓间充质干细胞、成骨细胞及破骨细胞等骨组织细胞的增殖及分化,通过靶向作用于相关成骨因子或骨吸收因子调控骨形成与骨吸收之间的平衡,在骨代谢的调控中发挥重要作用。近年的研究表明,调控miRNAs是运动或机械应力促进骨代谢正平衡的途径之一,运动能够诱导骨骼中miRNAs差异表达,进而调控相关成骨因子或骨吸收因子的表达,进一步加强运动的促成骨效应。本综述总结了运动介导miRNAs调控骨代谢的相关研究进展,为骨质疏松的运动防治提供理论基础。     

miR-214对骨形成的抑制作用

越来越多的研究表明microRNA广泛参与骨代谢的调控,调节骨髓间充质干细胞、成骨及破骨细胞的增殖及分化,调控骨形成与骨吸收之间的平衡,在维持骨代谢平衡中发挥重要作用。近年来有研究报道老年性骨质疏松、绝经后骨质疏松均与miR-214的高表达有关。miR-214通过靶向作用于Osterix、ATF-4、FGFR1、Pten以及LZTS1等基因调控骨髓间充质干细胞、成骨细胞以及破骨细胞等骨组织细胞的增殖及分化,进而抑制骨形成,促进骨吸收。本文主要综述了miR-214对骨髓间充质干细胞、成骨细胞以及破骨细胞分化的调控作用,旨在探讨miR-214对骨形成的抑制作用,为骨质疏松等骨疾病的诊断及治疗提供理论依据。     

miRNAs在破骨细胞中的研究进展

破骨细胞起源于造血干细胞,是体内一种负责骨吸收的骨特异性多核细胞,在骨代谢平衡的调控中起着重要作用。破骨细胞的分化形成及功能活性异常可引起一系列临床疾病,而其分化形成过程受到多种因子的调控,近年来越来越多研究聚焦于miRNAs对破骨细胞分化形成过程的调控作用。因此,本文主要对影响破骨细胞分化形成的相关miRNAs进行综述,为后续相关研究提供参考。     

lncRNAs调控破骨细胞分化的研究进展

长链非编码RNA (long noncoding RNAs, lncRNA)是一类长度大于200个核苷酸的非编码RNA,调控转录和转录后的基因表达,在各种生命活动过程中都起着重要的作用。破骨细胞是一种组织特异性的多核巨噬细胞,受多种信号因子和信号通路的调控,作为人体唯一的骨吸收细胞对维持骨代谢平衡具有非常重要的作用,当平衡被打破时则会引起一系列骨代谢疾病,如骨质疏松症、骨硬化症等。近些年研究发现,lncRNAs在破骨细胞分化过程中呈现差异化表达,且在其增殖、分化、凋亡过程中具有多重调控作用。该文就lncRNAs调控破骨细胞分化和功能的机制进行归纳总结,为破骨细胞功能异常所造成的骨代谢疾病提供新的研究靶点和诊疗思路。     

OPG/RANKL/RANK系统与骨破坏性疾病

近年来发现的OPG/RANKL/RANK系统在破骨细胞生成中起着至关重要的作用,是骨骼生理研究领域的重大进展。成骨细胞、骨髓基质细胞、激活的T淋巴细胞表达RANKL,与破骨细胞前体细胞或成熟破骨细胞表面上的RANK结合后,促进破骨细胞的分化及骨吸收活性。成骨细胞及骨髓基质细胞分泌表达OPG可与RANKL竞争性结合,从而阻断RANKL与RANK之间的相互作用。体内多种激素或因子通过影响骨髓微环境内的OPG/RANKL比率来调节骨代谢。此外,乳腺上皮细胞表达有RANK,孕期在性激素的诱导下可表达RANKL,OPG/RANKL/RANK系统在孕期乳腺发育以及母体向胎儿的钙转运过程中发挥重要作用。阻断RANKL/RANK通路有望给骨质疏松、类风湿关节炎及癌症骨转移等骨破坏性疾病的治疗开辟新的途径。进一步研究应了解OPG/RANKL/RANK系统与其它信号传导途径的关系,重视骨骼、免疫及内分泌系统之间的相互作用。目前,开发与OPG功能相似或促进其表达的合成药物有可能成为具有良好经济效益和社会效益的产业。     

微小RNA调控骨髓间充质干细胞成骨分化的研究进展

骨髓间充质干细胞(bone marrow mesenchymal stem cells,BMSCs)是机体内具有多向分化能力及自我更新能力的成体干细胞,具有自身增殖能力强、分化范围广的特点。其具有多种分化潜能,其中可分化为成骨细胞或成脂细胞,所以如何提高BMSCs向成骨细胞分化受到了越来越多研究者的关注。随着表观遗传学研究的逐步深入,研究人员对骨代谢相关微小RNA(microRNAs)的作用靶基因、信号通路等进行了大量研究,发现miRNAs是调节BMSCs成骨诱导分化的关键调控因子,在调控骨组织代谢性疾病方面具有重要意义。本研究将对miRNAs调控BMSCs成骨分化的相关因子及信号通路的研究进展进行综述。     

钙敏感受体在骨代谢中的研究进展

钙敏感受体感受细胞外的钙离子水平,调控一系列激素的释放以维持机体的钙稳态。钙稳态的调节过程与骨代谢相偶联,钙敏感受体通过直接或间接对破骨和成骨细胞的调控,动员或者抑制骨钙入血。虽然钙敏感受体已被证实调控骨代谢,但是详尽的调控机制仍在不断探究中。目前认为细胞外的高钙水平会激活钙敏感受体,抑制甲状旁腺激素分泌并促进降钙素释放,进而破骨细胞被抑制,成骨细胞动员,增加了骨质合成。本文就近年来关于钙敏感受体调控骨代谢的研究进展作一综述,为促进钙敏感受体及相关作用因子治疗骨代谢疾病的研究提供参考。     

DNA甲基化与骨代谢调节及骨质疏松症研究进展

骨质疏松症的根本病因是由于多种因素导致成骨细胞介导的骨形成与破骨细胞介导的骨吸收过程之间的负平衡,引起骨质进行性丢失,骨密度降低,骨脆性增加,进而导致骨折风险增加。越来越多的研究表明,DNA甲基化可通过调控相关基因表达调节成骨细胞/破骨细胞的分化与功能,进而影响骨形成/骨吸收平衡,介导骨质疏松症的发生、发展。现主要阐述DNA甲基化与骨代谢调节和骨质疏松症之间的关系,并对相关研究进展进行综述。     

microRNA在衰老性肌萎缩和运动干预中的调节作用

衰老性肌萎缩症是由于衰老所致的骨骼肌质量减少及功能减退的增龄性机能退化症,运动干预是其防治的最有效措施之一。研究表明,microRNAs (miRNAs)作为基因表达的调控因子,通过调节骨骼肌发育(增殖、分化)、线粒体生物发生、蛋白质合成与降解、炎症反应和代谢途径来维持衰老骨骼肌细胞稳态。此外,运动可改变miRNAs表达水平,调节骨骼肌细胞的代谢平衡,从而改善衰老相关的骨骼肌质量、组成和功能的变化。本文综述了miRNAs在衰老性肌萎缩症中的调节机制,阐述在运动条件下miRNAs在衰老性肌萎缩症中的调控作用和分子机制,以期为预防和治疗衰老性肌萎缩症提供新的思路。     

雄激素和雄激素受体对骨代谢的调控及机制研究进展

骨代谢由成骨细胞介导的骨形成和破骨细胞介导的骨吸收构成。雄激素能调控骨代谢,即促进骨形成、抑制骨吸收,在骨骼生长、骨峰值的获得和骨量维持中起重要作用;且该作用主要通过雄激素受体(androgen receptor,AR)介导。AR调控骨代谢的作用,一方面是通过直接调控骨代谢相关的AR靶基因(如与成骨相关的I型胶原蛋白α1、骨钙素、组织非特异性碱性磷酸酶、小整合素结合配体N-端连接糖蛋白和与破骨相关的核因子κB受体活化因子配体(RANKL)、组织蛋白酶K的表达;另一方面是通过间接调控骨代谢的多个信号通路[如Wnt/β-catenin、骨形态发生蛋白(BMP)/Smads-Runt相关转录因子2(Runx2)、RANKL/骨保护蛋白(OPG)、PI3K/Akt和MAPK信号通路]实现的。该文主要就雄激素/AR在骨代谢调控中的作用及机制作一综述,对丰富AR调控骨代谢的理论认识和骨代谢性疾病的药物研发具有重要意义。     

Expression profiling of microRNAs in human bone tissue from postmenopausal women

Bone tissue is composed of several cell types, which express their own microRNAs (miRNAs) that will play a role in cell function. The set of total miRNAs expressed in all cell types configures the specific signature of the bone tissue in one physiological condition. The aim of this study was to explore the miRNA expression profile of bone tissue from postmenopausal women. Tissue was obtained from trabecular bone and was analyzed in fresh conditions (n = 6). Primary osteoblasts were also obtained from trabecular bone (n = 4) and human osteoclasts were obtained from monocyte precursors after in vitro differentiation (n = 5). MicroRNA expression profiling was obtained for each sample by microarray and a global miRNA analysis was performed combining the data acquired in all the microarray experiments. From the 641 miRNAs detected in bone tissue samples, 346 (54%) were present in osteoblasts and/or osteoclasts. The other 46% were not identified in any of the bone cells analyzed. Intersection of osteoblast and osteoclast arrays identified 101 miRNAs shared by both cell types, which accounts for 30–40% of miRNAs detected in these cells. In osteoblasts, 266 miRNAs were detected, of which 243 (91%) were also present in the total bone array, representing 38% of all bone miRNAs. In osteoclasts, 340 miRNAs were detected, of which 196 (58%) were also present in the bone tissue array, representing 31% of all miRNAs detected in total bone. These analyses provide an overview of miRNAs expressed in bone tissue, broadening our knowledge in the microRNA field.     

Osteoclast Derivation from Mouse Bone Marrow

Osteoclasts are highly specialized cells that are derived from the monocyte/macrophage lineage of the bone marrow. Their unique ability to resorb both the organic and inorganic matrices of bone means that they play a key role in regulating skeletal remodeling. Together, osteoblasts and osteoclasts are responsible for the dynamic coupling process that involves both bone resorption and bone formation acting together to maintain the normal skeleton during health and disease.As the principal bone-resorbing cell in the body, changes in osteoclast differentiation or function can result in profound effects in the body. Diseases associated with altered osteoclast function can range in severity from lethal neonatal disease due to failure to form a marrow space for hematopoiesis, to more commonly observed pathologies such as osteoporosis, in which excessive osteoclastic bone resorption predisposes to fracture formation.An ability to isolate osteoclasts in high numbers in vitro has allowed for significant advances in the understanding of the bone remodeling cycle and has paved the way for the discovery of novel therapeutic strategies that combat these diseases. Here, we describe a protocol to isolate and cultivate osteoclasts from mouse bone marrow that will yield large numbers of osteoclasts.     

调控软骨形成的信号通路及相关因子在骨髓间充质干细胞骨向分化中的作用*

骨髓间充质干细胞是一类具有自我复制和多向分化潜能的成体干细胞,可以通过定向诱导分化为成骨细胞、软骨细胞、脂肪细胞等,是目前骨再生医学和细胞治疗研究最多的理想种子细胞。在骨缺损的修复过程中,骨髓间充质干细胞内成软骨相关基因表达升高进而分化为软骨细胞,后期随着成骨细胞和破骨细胞的形成及血管长入,软骨基质逐步降解并被骨基质所替换。软骨细胞参与了骨缺损前期的修复过程,调控软骨形成的信号通路及相关因子不仅调控骨髓间充质干细胞成软骨细胞分化,同时在成骨细胞分化过程中也发挥着重要的作用。对调控软骨形成的信号通路及相关因子在骨髓间充质干细胞骨向分化中的调控作用和研究现状进行了总结,以期为临床寻找更好的治疗骨缺损的方法提供理论依据和研究方向。     

Maintenance of Bone Homeostasis by DLL1‐Mediated Notch Signaling

Adult bone mass is maintained through a balance of the activities of osteoblasts and osteoclasts. Although Notch signaling has been shown to maintain bone homeostasis by controlling the commitment, differentiation, and function of cells in both the osteoblast and osteoclast lineages, the precise mechanisms by which Notch performs such diverse and complex roles in bone physiology remain unclear. By using a transgenic approach that modified the expression of delta‐like 1 (DLL1) or Jagged1 (JAG1) in an osteoblast‐specific manner, we investigated the ligand‐specific effects of Notch signaling in bone homeostasis. This study demonstrated for the first time that the proper regulation of DLL1 expression, but not JAG1 expression, in osteoblasts is essential for the maintenance of bone remodeling. DLL1‐induced Notch signaling was responsible for the expansion of the bone‐forming cell pool by promoting the proliferation of committed but immature osteoblasts. However, DLL1‐Notch signaling inhibited further differentiation of the expanded osteoblasts to become fully matured functional osteoblasts, thereby substantially decreasing bone formation. Osteoblast‐specific expression of DLL1 did not alter the intrinsic differentiation ability of cells of the osteoclast lineage. However, maturational arrest of osteoblasts caused by the DLL1 transgene impaired the maturation and function of osteoclasts due to a failed osteoblast‐osteoclast coupling, resulting in severe suppression of bone metabolic turnover. Taken together, DLL1‐mediated Notch signaling is critical for proper bone remodeling as it regulates the differentiation and function of both osteoblasts and osteoclasts. Our study elucidates the importance of ligand‐specific activation of Notch signaling in the maintenance of bone homeostasis. J. Cell. Physiol. 232: 2569–2580, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals Inc.     

Extracellular matrix networks in bone remodeling

Bones are constantly remodeled throughout life to maintain robust structure and function. Dysfunctional remodeling can result in pathological conditions such as osteoporosis (bone loss) or osteosclerosis (bone gain). Bone contains 100s of extracellular matrix (ECM) proteins and the ECM of the various bone tissue compartments plays essential roles directing the remodeling of bone through the coupled activity of osteoclasts (which resorb bone) and osteoblasts (which produce new bone). One important role for the ECM is to serve as a scaffold upon which mineral is deposited. This scaffold is primarily type I collagen, but other ECM components are involved in binding of mineral components. In addition to providing a mineral scaffolding role, the ECM components provide structural flexibility for a tissue that would otherwise be overly rigid. Although primarily secreted by osteoblast-lineage cells, the ECM regulates cells of both the osteoblast-lineage (such as progenitors, mature osteoblasts, and osteocytes) and osteoclast-lineage (including precursors and mature osteoclasts), and it also influences the cross-talk that occurs between these two oppositional cells. ECM influences the differentiation process of mesenchymal stem cells to become osteoblasts by both direct cell-ECM interactions as well as by modulating growth factor activity. Similarly, the ECM can influence the development of osteoclasts from undifferentiated macrophage precursor cells, and influence osteoclast function through direct osteoclast cell binding to matrix components. This comprehensive review will focus on how networks of ECM proteins function to regulate osteoclast- and osteoblast-mediated bone remodeling. The clinical significance of these networks on normal bone and as they relate to pathologies of bone mass and geometry will be considered. A better understanding of the dynamic role of ECM networks in regulating tissue function and cell behavior is essential for the development of new treatment approaches for bone loss.