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microRNA-17-92 家簇对骨发育、骨重塑和骨代谢的调控作用
Regulation of microRNA-17-92 cluster on bone development, remodeling, and metabolism

- , 2017, DOI: 10.7507/1002-1892.201701068
Abstract: 目的 综述 microRNA-17-92 家簇对骨发育、骨重塑和骨代谢的调控作用。 方法 查阅国内外相关文献,从临床遗传表型、动物实验及细胞研究 3 个不同层面进行阐述,探讨其可能的调控机制。 结果 microRNA-17-92 家簇广泛参与生物体生理状态下的器官发育、病理状态下肿瘤的发生发展。近年研究表明,microRNA-17-92 家簇与其上游转录因子、下游靶蛋白组成错综复杂的分子信号网络精细调控骨骼生长发育、重塑和代谢。 结论 目前基础研究对 microRNA-17-92 家簇调控骨骼系统的发育、重塑和代谢过程机制有一定了解,但确切机制尚未明确。
Objective To review the regulation of microRNA-17-92 cluster on bone development, remodeling, and metabolism. Methods The related literature was reviewed. The clinical genetic phenotype, animal experiment, and cell research were illustrated so as to explore the possible regulatory mechanisms. Results MicroRNA-17-92 cluster is involved in physiological normal organs development, pathological neoplasm occurrence, and development. Recently, studies have shown that microRNA-17-92 cluster constitutes an intricate molecular signaling network with its upstream transcription factors and downstream targeting proteins, which controls bone development, remodeling, and metabolism exquisitely. Conclusion Present fundamental researches have certain understanding of the regulatory mechanisms of microRNA-17-92 cluster on bone development, remodeling, and metabolism. However, the exact mechanisms under these processes remain unknown.
NF90 in Posttranscriptional Gene Regulation and MicroRNA Biogenesis  [PDF]
Kiyoshi Masuda,Yuki Kuwano,Kensei Nishida,Kazuhito Rokutan,Issei Imoto
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140817111
Abstract: Gene expression patterns are effectively regulated by turnover and translation regulatory (TTR) RNA-binding proteins (RBPs). The TTR-RBPs control gene expression at posttranscriptional levels, such as pre-mRNA splicing, mRNA cytoplasmic export, turnover, storage, and translation. Double-stranded RNA binding proteins (DSRBPs) are known to regulate many processes of cellular metabolism, including transcriptional control, translational control, mRNA processing and localization. Nuclear factor 90 (NF90), one of the DSRBPs, is abundantly expressed in vertebrate tissue and participates in many aspects of RNA metabolism. NF90 was originally purified as a component of a DNA binding complex which binds to the antigen recognition response element 2 in the interleukin 2 promoter. Recent studies have provided us with interesting insights into its possible physiological roles in RNA metabolism, including transcription, degradation, and translation. In addition, it was shown that NF90 regulates microRNA expression. In this review, we try to focus on the function of NF90 in posttranscriptional gene regulation and microRNA biogenesis.
Regulation of MicroRNA Biogenesis: A miRiad of mechanisms
Brandi N Davis, Akiko Hata
Cell Communication and Signaling , 2009, DOI: 10.1186/1478-811x-7-18
Abstract: microRNAs (miRNAs) have been reported to control diverse aspects of biology, including developmental timing, differentiation, proliferation, cell death, and metabolism [1-3]. Because miRNAs exert these functions primarily through the repression of target genes, the determination of miRNA targets has been an area of intense research. Computational and experimental approaches indicate that a single miRNA may target several dozen or even hundreds of mRNA [4]. Additionally, more than 60% of human protein coding genes are predicted to contain miRNA binding sites within their 3' untranslated regions (UTRs) [4,5]. The diversity and number of miRNAs suggests that a vast number of normal and pathological outcomes may be controlled, at least in part, through miRNA-mediated repression. While some miRNAs are described as regulating developmental switches mediated through the repression of a single target, it is increasingly clear that the majority of miRNAs exert their effects through the modest reduction of a large number of targets which altogether give alterations in cellular phenotype [4,6].miRNAs select mRNA targets for down-regulation through the association with a large, multi-protein complex, the RNA Induced Silencing Complex (RISC). This selection requires the presence of sequences within the target mRNA which are imperfectly complementary to the miRNA sequence; miRNA binding sites commonly occur within the 3'-untranslated region (UTR) of the mRNA, but functional miRNA binding sites can also occur with the 5'UTR [7] or coding region [8]. Intriguingly, the presence of a miR-148 binding site within an alternatively-spliced exon of DNA (cytosine-5-)-methyltransferase 3 beta (Dmnt3b) can promote the differential expression of splice variants [9].The absence of perfect complementarity between the miRNA sequence and target sites complicates the identification of miRNA target genes. However, Watson-Crick base pairing between the target and the 5'-end of miRNAs, particularly t
Mechanobiological regulation of bone remodeling -- Theoretical development of a coupled systems biology-micromechanical approach  [PDF]
Stefan Scheiner,Peter Pivonka,Christian Hellmich,David W. Smith
Quantitative Biology , 2012,
Abstract: Bone remodeling involves the coordinated removal of bone by osteoclasts and addition of bone by osteoblasts, a process that is modulated by the prevailing mechanical environment. In this paper a fully coupled model of bone remodeling is developed, based on coupling a bone cell population model with a micromechanical homogenization scheme of bone stiffness. While the former model considers biochemical regulatory mechanisms between bone cells such as the RANK-RANKL-OPG pathway and action of TGF-\beta, the latter model allows for accurate upscaling of the mechanical properties of bone. Importantly, we consider bone remodeling as being controlled proportionally to the microscopic strain energy density, on the observation scale where the sensing of the mechanical loading takes place, estimated by means of continuum micromechanics-based strain concentration. This approach allows to address two fundamental questions of bone biology: (i) How do biochemical changes influence bone remodeling and so affect the composition and mechanical properties of bone? and (ii) What mechanisms are responsible for mechanoregulation of bone remodeling? Numerical studies highlight the conceptual advantage of this new approach compared to conventional phenomenological models. It is demonstrated that the proposed model is able to simulate changes of the bone constituent volume fractions that are in qualitative agreement with experimental observations for osteoporotic and disuse syndromes.
Versatility of MicroRNA Biogenesis  [PDF]
Naama Volk,Noam Shomron
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019391
Abstract: MicroRNAs (miRNAs) are short single-stranded RNA molecules that regulate gene expression. MiRNAs originate from large primary (pri) and precursor (pre) transcripts that undergo various processing steps along their biogenesis pathway till they reach their mature and functional form. It is not clear, however, whether all miRNAs are processed similarly. Here we show that the ratio between pre-miRNA and mature miRNA forms varies between different miRNAs. Moreover, over-expression of several factors involved in miRNA biogenesis, including Exportin-5, Drosha, NF90a, NF45 and KSRP, displayed bidirectional effects on pre/mature miRNA ratios, suggesting their intricate biogenesis sensitivity. In an attempt to identify additional factors that might explain the versatility in miRNA biogenesis we have analyzed the contribution of two hnRNP family members, hnRNPH1 and hnRNPR. Knock-down or over-expression of these genes suggested that hnRNPR inhibits, whereas hnRNPH1 facilitates, miRNA processing. Overall, our results emphasize that miRNA biogenesis is versatile.
Progress in the regulation of bone remodeling at the cellular level

- , 2017, DOI: 10.7507/1001-5515.201606011
Abstract: 骨重建是一个不断进行骨吸收与骨形成的平衡动态过程,需要成骨细胞和破骨细胞的紧密配合,并经由复杂的旁分泌和自分泌途径,被相关调节蛋白紧密地调控。骨细胞、骨被覆细胞、骨巨噬细胞以及血管内皮细胞在基础多细胞单位(BMU)中均通过配体-受体复合物的细胞信号网络参与到骨重建调节过程中。此外,T 淋巴细胞和 B 淋巴细胞通过处于骨微环境中的分泌型和膜结合型因子,也参与到骨重建过程中,在骨免疫中调节骨的内稳态。在骨重建的过程中,常由于 BMU 中的细胞间连接被破坏,导致多发骨质疏松症和其他骨疾病发生。本文主要从细胞水平上描述骨重建过程中的细胞间联系、分子基础和新型旁分泌或偶联因子,了解骨重建过程和相关基因,有助于对骨质疏松等骨科疾病的药物开发奠定基础。
Bone remodeling requires an intimate cross-talk between osteoclasts and osteoblasts and is tightly coordinated with regulatory proteins that interact through complex autocrine/paracrine processes. Osteocytes, bone lining cells, osteomacs and vascular endothelial cells also regulate bone remodeling in the basic multicellular unit (BMU) via cell signaling networks of ligand-receptor complexes. In addition, through secreted and membrane-bound factors in the bone microenvironment, T and B lymphocytes mediate bone homeostasis for osteoimmunology. Osteoporosis and other bone diseases occur because multicellular communication within the BMU is disrupted. This review focuses on the roles of the cells in the BMU and the interaction between these cells and the factors involved in regulating bone remodeling at the cellular level. Understanding the process of bone remodeling and related genes could help us to lay the foundation for drug development against bone diseases.
The evolution of core proteins involved in microRNA biogenesis
Dennis Murphy, Barry Dancis, James R Brown
BMC Evolutionary Biology , 2008, DOI: 10.1186/1471-2148-8-92
Abstract: Phylogenetic analyses show that all four miRNA pathway proteins were derived from large multiple protein families. As an example, vertebrate and invertebrate Argonaute (Ago) proteins diverged from a larger family of PIWI/Argonaute proteins found throughout eukaryotes. Further gene duplications among vertebrates after the evolution of chordates from urochordates but prior to the emergence of fishes lead to the evolution of four Ago paralogues. Invertebrate RISC RNA-binding proteins R2D2 and Loquacious are related to other RNA-binding protein families such as Staufens as well as vertebrate-specific TAR (HIV trans-activator RNA) RNA-binding protein (TRBP) and protein kinase R-activating protein (PACT). Export of small RNAs from the nucleus, including miRNA, is facilitated by three closely related karyopherin-related nuclear transporters, Exportin-5, Exportin-1 and Exportin-T. While all three exportins have direct orthologues in deutrostomes, missing exportins in arthropods (Exportin-T) and nematodes (Exportin-5) are likely compensated by dual specificities of one of the other exportin paralogues.Co-opting particular isoforms from large, diverse protein families seems to be a common theme in the evolution of miRNA biogenesis. Human miRNA biogenesis proteins have direct, orthologues in cold-blooded fishes and, in some cases, urochordates and deutrostomes. However, lineage specific expansions of Dicer in plants and invertebrates as well as Argonaute and RNA-binding proteins in vertebrates suggests that novel ncRNA regulatory mechanisms can evolve in relatively short evolutionary timeframes. The occurrence of multiple homologues to RNA-binding and Argonaute/PIWI proteins also suggests the possible existence of further pathways for additional types of ncRNAs.Recent studies have unveiled the critical roles that RNA interference (RNAi) mediated by small noncoding RNAs (ncRNAs) plays in the regulation of eukaryotic genes. One particular important ncRNA class is microRNA (miRNA
General analysis of mathematical models for bone remodeling  [PDF]
Martin Zumsande,Dirk Stiefs,Stefan Siegmund,Thilo Gross
Quantitative Biology , 2010,
Abstract: Bone remodeling is regulated by pathways controlling the interplay of osteoblasts and osteoclasts. In this work, we apply the method of generalized modelling to systematically analyse a large class of models of bone remodeling. Our analysis shows that osteoblast precursors can play an important role in the regulation of bone remodeling. Further, we find that the parameter regime most likely realized in nature lies very close to bifurcation lines, marking qualitative changes in the dynamics. Although proximity to a bifurcation facilitates adaptive responses to changing external conditions, it entails the danger of losing dynamical stability. Some evidence implicates such dynamical transitions as a potential mechanism leading to forms of Paget's disease.
The cellular dynamics of bone remodeling: a mathematical model  [PDF]
Marc Ryser,Svetlana V. Komarova,Nilima Nigam
Quantitative Biology , 2011,
Abstract: The mechanical properties of vertebrate bone are largely determined by a process which involves the complex interplay of three different cell types. This process is called {\it bone remodeling}, and occurs asynchronously at multiple sites in the mature skeleton. The cells involved are bone resorbing osteoclasts, bone matrix producing osteoblasts and mechanosensing osteocytes. These cells communicate with each other by means of autocrine and paracrine signaling factors and operate in complex entities, the so-called bone multicellular units (BMU). To investigate the BMU dynamics in silico, we develop a novel mathematical model resulting in a system of nonlinear partial differential equations with time delays. The model describes the osteoblast and osteoclast populations together with the dynamics of the key messenger molecule RANKL and its decoy receptor OPG. Scaling theory is used to address parameter sensitivity and predict the emergence of pathological remodeling regimes. The model is studied numerically in one and two space dimensions using finite difference schemes in space and explicit delay equation solvers in time. The computational results are in agreement with in vivo observations and provide new insights into the role of the RANKL/OPG pathway in the spatial regulation of bone remodeling.
NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling  [PDF]
Mikael S. Lindstr m
Biochemistry Research International , 2011, DOI: 10.1155/2011/195209
Abstract: At a first glance, ribosome biogenesis and chromatin remodeling are quite different processes, but they share a common problem involving interactions between charged nucleic acids and small basic proteins that may result in unwanted intracellular aggregations. The multifunctional nuclear acidic chaperone NPM1 (B23/nucleophosmin) is active in several stages of ribosome biogenesis, chromatin remodeling, and mitosis as well as in DNA repair, replication and transcription. In addition, NPM1 plays an important role in the Myc-ARF-p53 pathway as well as in SUMO regulation. However, the relative importance of NPM1 in these processes remains unclear. Provided herein is an update on the expanding list of the diverse activities and interacting partners of NPM1. Mechanisms of NPM1 nuclear export functions of NPM1 in the nucleolus and at the mitotic spindle are discussed in relation to tumor development. It is argued that the suggested function of NPM1 as a histone chaperone could explain several, but not all, of the effects observed in cells following changes in NPM1 expression. A future challenge is to understand how NPM1 is activated, recruited, and controlled to carry out its functions.
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