https://www.cell.com/trends/microbiology/pdf/S0966-842X(04)00264-1.pdf

Survival strategies of infectious biofilms.

Bone formation during skeletal development involves a complex coordination among multiple cell types and tissues. Bone is of crucial importance for the human body, providing skeletal support, and serving as a home for the formation of hematopoietic cells and as a reservoir for calcium and phosphate. Bone is also continuously remodeled in vertebrates throughout life. Osteoblasts and osteoclasts are specialized cells responsible for bone formation and resorption, respectively. Early development of the vertebrate skeleton depends on genes that control the distribution and proliferation of cells from cranial neural crest, sclerotomes, and lateral plate mesoderm into mesenchymal condensations, where cells differentiate to osteoblasts. Significant progress has been made over the past decade in our understanding of the molecular framework that controls osteogenic differentiation. A large number of morphogens, signaling molecules, and transcriptional regulators have been implicated in regulating bone development. A partial list of these factors includes the Wnt/beta-catenin, TGF-beta/BMP, FGF, Notch and Hedgehog signaling pathways, and Runx2, Osterix, ATF4, TAZ, and NFATc1 transcriptional factors. A better understanding of molecular mechanisms behind osteogenic differentiation would not only help us to identify pathogenic causes of bone and skeletal diseases but also lead to the development of targeted therapies for these diseases.

Regulation of osteogenic differentiation during skeletal development.

Epigenetic mechanisms play a crucial role in regulating gene expression. The main mechanisms involve methylation of DNA and covalent modifications of histones by methylation, acetylation, phosphorylation, or ubiquitination. The complex interplay of different epigenetic mechanisms is mediated by enzymes acting in the nucleus. Modifications in DNA methylation are performed mainly by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, while a plethora of enzymes, such as histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and histone demethylases (HDMs) regulate covalent histone modifications. In many diseases, such as cancer, the epigenetic regulatory system is often disturbed. Vitamin D interacts with the epigenome on multiple levels. Firstly, critical genes in the vitamin D signaling system, such as those coding for vitamin D receptor (VDR) and the enzymes 25-hydroxylase (CYP2R1), 1α-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1) have large CpG islands in their promoter regions and therefore can be silenced by DNA methylation. Secondly, VDR protein physically interacts with coactivator and corepressor proteins, which in turn are in contact with chromatin modifiers, such as HATs, HDACs, and HMTs, and with chromatin remodelers. Thirdly, a number of genes encoding for chromatin modifiers and remodelers, such as HDMs of the Jumonji C (JmjC)-domain containing proteins and lysine-specific demethylase (LSD) families are primary targets of VDR and its ligands. Finally, there is evidence that certain VDR ligands have DNA demethylating effects. In this review we will discuss regulation of the vitamin D system by epigenetic modifications and how vitamin D contributes to the maintenance of the epigenome, and evaluate its impact in health and disease.

/pdf/vitamin-d-and-the-epigenome-3gzscvgjg4.pdf

Vitamin D and the epigenome

Mesenchymal stem cells (MSCs) are multipotent cells that arise from the mesenchyme during development. They reside in the bone marrow close to hematopoietic stem cell niches allowing them to maintain bone marrow homeostasis and to regulate the maturation of both hematopoietic and non-hematopoietic cells. MSCs possess an extensive potential to proliferate and differentiate e.g. into osteoblasts, osteocytes, adipocytes and chondrocytes. Nevertheless, there still are some open questions about the complex process of MSC differentiation involving different transcription factors and signaling pathways, which will be discussed in this review. We also shortly introduce the characteristics and function of bone-forming osteoblasts and their role in angiogenesis. MSCs are of interest in clinical applications, since they can be easily isolated from bone marrow aspirates and expanded in vitro. When the source of osteoprogenitors is compromised, cell-based therapies could provide a novel way to repair bone defects. Indeed, there is an increasing interest in the use of MSCs and more differentiated cells in clinical applications for bone repair, which will be introduced in this review. A major section of the review is dedicated to the functions of osteocytes in the regulation of bone remodeling. Finally, we present an original hypothesis about the possible role of osteocytes in future bone tissue engineering.

Differentiation of osteoblasts and osteocytes from mesenchymal stem cells.

Cancer metastasis is the leading cause of cancer-related deaths all over the world at present. Accumulated researches have demonstrated that cancer metastasis is composed of a series of successive incidents, mainly including epithelial-mesenchymal transition (EMT), malignant cell migration, resistance to anoikis, and angiogenesis and lymphangiogenesis processes. However, the complicated cellular and molecular mechanisms underlying and modulating these processes have not been well elucidated. Thus, studies on cancer metastasis mechanism may propose possibilities to therapeutically interfere with signaling pathways required for each step of cancer metastasis, therefore inhibiting the outgrowth of distant metastasis of tumors. Recent insights have linked the Notch signaling pathway, a critical pathways governing embryonic development and maintaining tumor stemness, to cancer metastasis. This chapter highlights the current evidence for aberration of the Notch signaling in metastasis of tumors such as osteosarcoma, breast cancer, prostate cancer, and melanoma. In these studies, Notch activity seems to participate in cancer metastasis by modulating the EMT, tumor angiogenesis processes, and the anoikis-resistance of tumor cells. Therefore, manipulating Notch signaling may represent a promising alternative/ complement therapeutic strategy targeting cancer metastasis besides cancer stemness.

Notch signaling pathway and cancer metastasis.

Background: The classification of proximal humeral fractures is a quite difficult problem. Both the Neer and the AO classification meet the requirements of a reliable classification system only in a limited form. In order to devise a more systematic, precise and reproducible classification system, the MTM classification = modular topographic and morphologic classification has been developed. It is based on an alphanumeric code. Standardized and good-quality anteroposterior and axillary radiographs are one of the main prerequisites for correct topographic and morphologic fracture assessment. In addition, fracture stability testing under fluoroscopic C-arm visualization and the use of CT scan may be necessary. 
Topographic Classification: The fractures are classified according to their determining topography into type A fractures = extraarticular, type B fractures = incomplete articular, and type C fractures = complete articular. The risk of avascular head necrosis increases from A to B and from B to C. The A, B, and C fractures are further classified topographically according to the fractures in the extraarticular segment, which are coded as G fractures = fractures of the greater tuberosity, L fractures = fractures of the lesser tuberosity, and M fractures = metaphyseal fractures. The fracture-dislocations are integrated in the MTM classification system and coded with the letter D. 
Morphologic Classification: The morphologic part of the classification is based on a catalog with four specifications, relevant for therapy and prognosis, arranged in the order of increasing severity: S1 = minimally displaced and stable; S2 = minimally displaced and unstable; S3 = displaced; S4 = displaced and comminuted. Defined criteria exist for the specifications and their practical application. In case of fractures with several main fragments, each single fracture is specified individually.

Suggestion for a Modular Topographic-Morphologic Classification of Proximal Humeral Fractures

The aim of the present study was to detect differentially expressed genes in the human osteoblast-like osteosarcoma cell line SaOS-2 using non-radioactive RNA fingerprinting (RNA arbitrarily primed polymerase chain reaction, RAP-PCR). RNA was isolated at different time points from SaOS-2 cells grown with and without dexamethasone (DEX). By RAP-PCR we detected changes in band patterns of cells treated with DEX compared with untreated cells. PCR fragments further characterized and sequences from three of these gave perfect matches to the coding sequences of the human nucleophosmin gene B23, cDNA clone 4_c6 from P1 H25 and the human TRA1 gene, respectively. differential regulation of these genes in DEX-stimulated SaOS-2 cells could be demonstrated by RT-PCR.

Detection of differential gene expression in human osteoblastic cells by non-radioactive RNA arbitrarily primed PCR.

Hintergrund: Zur ACT werden HAC zur Zellzahlvermehrung kultiviert. Darunter nehmen die Zellen ein fibroblastenahnliches Aussehen an und verlieren ihre knorpelspezifischen Eigenschaften. Das gesamte Ausmas der Veranderungen und die Reversibilitat sind ungeklart.

Differentielle Genexpression humaner artikulärer Chondrozyten in Monolayerkultur

Differentielle Genexpression humaner artikuUirer Chondrozyten in Monolayerkultur Differential gene expression of cultured human articular chondrocytes

Notch receptors participate in a conserved signaling pathway that controls the development of diverse tissues and cell types. In the present study we investigated the expression of four Notch genes in primary human osteoblasts and in human osteoblastic osteosarcoma cell line SaOS-2 by RT-PCR. We found a strong constitutive expression of Notch-1 and a weak constitutive expression of Notch-2 in both cell types. After stimulation with Dexamethasone or Vitamin D(3), two factors known to induce differentiation in osteogenic cells, both Notch receptors were downregulated, however, with a different time course. Notch-1 and Notch-2 showed a transient induction after 2 days and a decrease after 7 days in osteoblasts and after 28 days in SaOS-2 cells. Notch-4 expression could only be detected after stimulation with Dexamethasone and Vitamin D(3). However, in osteoblasts a transient induction after 2 days could be detected in osteoblasts, whereas Notch-4 expression increased after 14 and 28 days in SaOS-2 cells. In contrast, Notch-3 was not expressed in human osteoblasts and SaOS-2 osteosarcoma cells. These data show, that Notch genes are expressed in human osteoblastic cells and that the expression is differentially regulated upon stimulation with osteogenic factors.

Differential expression of Notch genes in human osteoblastic cells.

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