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。     

Wnt/β-catenin信号通路在运动调控骨形成中的机制

骨形成是成骨细胞(osteoblast, OB)合成和分泌骨基质,进而矿化形成新骨的过程。研究表明,运动能够通过外部机械应力、机体内分泌激素水平调节、表观遗传等方式调控骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)分化命运,促进骨形成,在不同生理、病理条件下改善骨量。Wnt/β-catenin信号通路与“运动因子”交互作用,既能通过抑制骨硬化蛋白(osteosclerosis, SOST)和Dickkopf相关蛋白1 (Dickkopf-related protein 1, DKK1),促进Wnt配体及其受体(LRP5/6)基因的表达,激活β-catenin下游信号转导;也能通过促进和(或)抑制相关细胞因子和激素的分泌及调控非编码RNA (non-coding RNA, ncRNA)等方式,间接激活Wnt/β-catenin信号通路。该文系统梳理了不同形式的运动对Wnt/β-catenin通路的调控作用,探讨了该通路在运动调控骨形成过程中的具体作用机制,以期为运动防治骨代谢相关疾病及药物靶点的研发提供理论参考。     

OPG、RANK、RANKL的结构、作用机制和在骨疾病中的作用

破骨细胞和成骨细胞分别介导骨的吸收过程和合成过程,而OPG、RANK、RANKL在调节二者的比例中发挥非常重要的作用.RANKL与RANK结合后可能通过三种途径:JNK途径、NF-κB途径和蛋白激酶B途径参与破骨细胞的分化,促进骨质的吸收;RANKL与OPG结合后能阻断RANKL与RANK的结合,由于缺乏RANKL-RANK产生的转录活化信号,破骨细胞分化成熟发生障碍,骨质的吸收受到抑制.OPG、RANK、RANKL同时也是免疫分子,在淋巴细胞、淋巴器官的分化、发育中起重要的作用,骨疾病与免疫系统之间存在着一定的关系.RANMKL/RANK与RANKI/OPG在生物体内保持着一定的比率,如果比率失衡,就会引起各种骨疾病.本篇综述总结了近年来OPG、RANK、RANKL结构、作用的新进展以及它们在骨疾病中的作用.     

成骨细胞的骨形成调控机制

成骨细胞在骨的形成、发育、改建、修复过程中发挥重要作用,多种生长因子可影响成骨细胞的增殖、分化及其合成细胞外基质的作用。多种生长因子对成骨细胞的作用既有相同之处,也有不同点。寻找一种或联合应用几种不同的生长因子达到既能促进成骨细胞增殖又保持其成骨活性将是今后研究的热点。     

microRNAs——脂质代谢调控新机制

综述了近年来microRNAs,尤其是miR-33在脂质代谢调控方面的功能研究进展.脂质代谢在细胞水平进行有规律的调控,主要参与者有肝X受体(LXRs)和固醇调节元件结合蛋白(SREBPs)等.最近研究发现,非编码RNAs家族成员microRNAs在转录后水平调节脂质代谢相关基因表达,参与胆固醇、甘油三酯和脂肪酸代谢.其中miR-33可靶向沉默三磷酸脂苷结合盒(ABC)转运体家族成员ABCA1和ABCG1,抑制胆固醇流出和高密度脂蛋白(HDL)合成;通过靶向沉默脂肪酸β-氧化相关基因,如CPT1A、CROT和HADHB表达,抑制脂肪酸氧化;还可沉默AMPK和RIP140的表达,影响甘油三酯代谢.其他microRNAs如miR-122、miR-370、miR-125a-5p、miR-27、miR-320等,也参与调控胆固醇、甘油三脂、脂肪酸代谢及脂肪细胞分化.     

破骨细胞在类风湿性关节炎骨破坏中的作用及其调控机制

类风湿性关节炎 (RA)是一种严重的慢性炎症性疾病 ,关节软骨及骨的破坏是患者致残的主要原因。近年大量相关研究表明 ,破骨细胞 (OC)在RA骨破坏的病理过程中起关键作用。多种细胞因子参与了对OC生成、活化的调控。其中起正调控作用的主要有IL 1、TNFα、RANKL、M CSF、IL 6、IL 8、IL 17、IL 7、IL 11、IL 15等 ,起负调控作用的有OPG、IL 4、IL 10、IL 12、IL 13、IL 18、IFN λ等。OC及其调控因子的研究为RA骨破坏的治疗提供了一些潜在的靶点 ,具有重要的理论意义和实用价值     

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。     

microRNAs在肿瘤免疫中的调控作用

microRNAs（miRNAs）是一类转录后调控基因表达的内源性非编码微小RNA。愈来愈多的研究显示,miRNAs在肿瘤免疫应答中发挥重要调控作用。一方面,miRNAs通过转录后调控ICAM（intercellular adhesion molecule）、B7（CD80／86）和HLA—G（human leucocyte antigen—G）等肿瘤表面分子的表达,影响肿瘤的免疫原性;另一方面,miRNAs通过平衡肿瘤局部的细胞因子微环境或调控肿瘤免疫相关细胞的分化、发育及功能发挥,调节机体抗肿瘤免疫应答。为后续深入研究肿瘤与宿主的相互作用机制,以及发展更有效的肿瘤生物治疗手段,就目前miRNAs在肿瘤免疫中的调控作用的研究进展做一综述。     

骨吸收与骨形成耦联中Eph/ephrin信号转导的研究进展

破骨细胞的骨吸收活动与成骨细胞的骨形成活动相互作用调节,形成一种特殊的耦联机制,影响骨骼生长、发育及正常骨组织结构的维持．最近几年提出的Eph/ephrin双向信号转导在骨吸收与骨形成耦联中的研究越来越受到关注．从Eph/ephrin分子结构、信号转导机制及生物学意义等几方面对该理论作一阐述．     

HIF-1α在骨组织细胞代谢及骨疾病中的调控作用

低氧诱导因子-1α(HIF-1α)是调节细胞对低氧应答的关键因子,可在氧含量降低时被激活,能够调节氧代谢、糖酵解等多种生理活动.骨代谢主要包括骨形成和骨吸收作用,均受到氧浓度等多种因素的调控.HIF-1α在细胞代谢、骨组织生理及病理过程的调控中起着重要的作用,能够增加骨组织的低氧耐受能力,调节骨形成和矿化过程.该文主要...     

综述与专论：膜上G蛋白偶联受体在运动影响骨代谢中的作用

膜上G蛋白偶联受体（GPCRs）是骨细胞感知外部信号刺激的关键跨膜蛋白,因其在成骨细胞（OB）、软骨细胞和破骨细胞（OC）分化和功能发挥上扮演的关键角色而在骨代谢研究领域备受关注。GPCRs功能缺失或异常升高后,骨细胞内环境稳态失衡,导致OB、软骨细胞和OC分化及代谢紊乱,骨组织微细结构退化。运动通过促进骨形成并抑制骨吸收来改善骨代谢,其机制与GPCRs （如GPR48、GPR54、GPR30等）介导的关键信号途径（cAMP/PKA/Atf4、JNK/AP-1、ERK1/2等）和细胞因子（T-PINP、Nkx3.2、Sox9和Cleaved-caspase-3等）调控下游级联反应来影响OB、软骨细胞和OC分化或功能密切相关。本文通过梳理GPCRs在运动改善骨代谢中的可能机制,有助于筛选出膜上敏感GPCRs来作为骨代谢疾病药物研发“效应器”以及运动干预中的力学刺激“明星蛋白”,为骨质疏松的研究和防治提供更多靶点或视角。     

Role of active and latent transforming growth factor β in bone formation

At first reading the statement “TGFβ stimulates bone formation but inhibits mineralization” may appear to be an oxymoron. However, the bone formation process can take weeks to months to complete, and the unique properties of TGFβ allow this factor to be stored in bone matrix in a latent form, ready to be activated and inactivated at key, pivotal stages in this long process. TGFβ may act to trigger the cascade of events that ultimately leads to new bone formation. However, once this process is initiated, TGFβ must then be inactivated or removed because if present in the later stages of bone formation, mineralization will be inhibited. The unique properties of TGFβ and its role in bone remodeling are the subject of this review. © 1994 Wiley-Liss, Inc.     

斯钙素在哺乳动物骨组织代谢中的作用

斯钙素（stanniocalcin,STC）是一种最早在硬骨鱼中发现的糖蛋白类激素. 哺乳动物斯钙素在体内钙磷代谢、肌肉骨骼系统的发育等方面均起到重要作用,并且在心血管疾病、肿瘤发展以及神经系统疾病中也扮演重要角色. 近年,斯钙素在骨骼发育中的作用逐渐引起科学界的关注. 骨组织中STC由成软骨细胞、成骨细胞分泌,并以自分泌/旁分泌的形式作用于局部组织细胞中,主要影响软骨形成和骨重建过程.本文以斯钙素为主题,综述了其生化分子特性、其在骨组织中的表达分布特点,以及该分子在成熟骨组织骨重建过程中的作用机制. 本文将为深入了解斯钙素在骨组织代谢中的作用提供帮助.     

Effects and Mechanisms of Exogenous Electromagnetic Field on Bone Cells: A Review

Osteoporosis, fractures, and other bone diseases or injuries represent serious health problems in modern society. A variety of treatments including drugs, surgeries, physical therapies, etc. have been used to prevent or delay the progression of these diseases/injuries with limited effects. Electromagnetic field (EMF) has been used to non-invasively treat bone diseases, such as fracture and osteoporosis, for many years. However, because a variety of cellular and molecular events can be affected by EMF with various parameters, the precise bioeffects and underlying mechanisms of specific EMF on bone cells are still obscure. Here, we summarize the common therapeutic parameters (frequency and intensity) of major types of EMF used to treat bone cells taken from 32 papers we selected from the PubMed database published in English from 1991 to 2018. Briefly, pulse EMF promotes the proliferation of osteoblasts when its frequency is 7.5–15 Hz or 50–75 Hz and the intensity is 0.40–1.55 mT or 3.8–4 mT. Sinusoidal EMF, with 0.9–4.8 mT and 45–60 Hz, and static magnetic field with 0.1–0.4 mT or 400 mT, can promote osteoblast differentiation and maturation. Finally, we summarize the latest advances on the molecular signaling pathways influenced by EMF in osteoblasts and osteoclasts. A variety of molecules such as adenosine receptors, calcium channels, BMP2, Notch, Wnt1, etc., can be influenced by EMF in osteoblasts. For osteoclasts, EMF affects RANK, NF-κB, MAPK, etc. We speculate that EMF with different frequencies and intensities exert distinct bioeffects on specific bone cells. More high-quality work is required to explore the detailed effects and underlying mechanisms of EMF on bone cells/skeleton to optimize the application of EMF on bone diseases/injuries. Bioelectromagnetics. 2020;41:263–278 © 2020 Bioelectromagnetics Society.     

Involvement of serum‐derived exosomes of elderly patients with bone loss in failure of bone remodeling via alteration of exosomal bone‐related proteins

Exosomes are secreted into the blood by various types of cells. These extracellular vesicles are involved in the contribution of exosomal proteins to osteoblastic or osteoclastic regulatory networks during the failure of bone remodeling, which results in age‐related bone loss. However, the molecular changes in serum‐derived exosomes (SDEs) from aged patients with low bone density and their functions in bone remodeling remain to be fully elucidated. We present a quantitative proteomics analysis of exosomes purified from the serum of the elderly patients with osteoporosis/osteopenia and normal volunteers; these data are available via Proteome Xchange with the identifier PXD006463. Overall, 1,371 proteins were identified with an overlap of 1,160 Gene IDs among the ExoCarta proteins. Bioinformatics analysis and in vitro studies suggested that protein changes in SDEs of osteoporosis patients are not only involved in suppressing the integrin‐mediated mechanosensation and activation of osteoblastic cells, but also trigger the differentiation and resorption of osteoclasts. In contrast, the main changes in SDEs of osteopenia patients facilitated both activation of osteoclasts and formation of new bone mass, which could result in a compensatory elevation in bone remodeling. While the SDEs from aged normal volunteers might play a protective role in bone health through facilitating adhesion of bone cells and suppressing aging‐associated oxidative stress. This information will be helpful in elucidating the pathophysiological functions of SDEs and aid in the development of senile osteoporosis diagnostics and therapeutics.     

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。     

Convergent metatarsal fusion in jerboas and chickens is mediated by similarities and differences in the patterns of osteoblast and osteoclast activities

In many vertebrate animals that run or leap, the metatarsals and/or metacarpals of the distal limb are fused into a single larger element, likely to resist fracture due to high ground‐reaction forces during locomotion. Although metapodial fusion evolved independently in modern birds, ungulates, and jerboas, the developmental basis has only been explored in chickens, which diverged from the mammalian lineage approximately 300 million years ago. Here, we use a bipedal rodent, the lesser Egyptian jerboa (Jaculus jaculus), to understand the cellular processes of metatarsal fusion in a mammal, and we revisit the developing chicken to assess similarities and differences in the localization of osteoblast and osteoclast activities. In both species, adjacent metatarsals align along flat surfaces, osteoblasts cross the periosteal membrane to unite the three elements in a single circumference, and osteoclasts resorb bone at the interfaces leaving a single marrow cavity. However, the pattern of osteoclast activity differs in each species; osteoclasts are highly localized to resorb bone at the interfaces of neighboring jerboa metatarsals and are distributed throughout the endosteum of chicken metatarsals. Each species, therefore, provides an opportunity to understand mechanisms that pattern osteoblast and osteoclast activities to alter bone shape during development and evolution.     

强直性脊柱炎新骨形成机制研究进展

强直性脊柱炎（Ankylosing spondylitis, AS）是以骶髂关节和脊柱病变为主的炎性疾病。其特征性病理表现为炎症和新骨形 成。近年来使用肿瘤坏死因子（Tumor necrosis factor,TNF）抑制剂控制AS 炎症已卓有成效,却无法阻止影像学进程,其病理性新 骨形成可致残,严重影响患者健康生活,但其机制尚不完全清楚。目前研究认为复杂的新骨形成机制与Wnt/beta-catenin信号通路及 其调控因子、炎症介质密切相关。本文结合当前国内外的研究就AS 新骨形成机制进展展开综述,为深入研究新骨形成机制提供 新思想。