Roles for CCN2 in normal physiological processes

CCN2, also known as connective tissue growth factor, is a member of the CCN (CCN1–6) family of modular matricellular proteins. Analysis of CCN2 function in vivo has focused primarily on its key role as a mediator of excess ECM synthesis in multiple fibrotic diseases. However, CCN2 and related family members are widely expressed during development. Recent studies using new genetic models are revealing that CCN2 has essential roles in the development of many tissues. This review focuses on current and emerging data on CCN2 and its functions in chondrogenesis and angiogenesis, and on new studies showing that CCN2 has essential functions during embryonic and postnatal development in a number of epithelial tissues.     

Common Molecular Mechanisms of Mammary Gland Development and Breast Cancer

Hypoxia affects many important processes in tumour progression and is a key feature in the tumour microenvironment that needs to be taken into account when evaluating prognostics and therapeutic options for cancer patients. Hypoxia-regulating proteins, i.e. hypoxia inducible factors (HIFs), and associated gene products have been linked to certain tumour behaviours and might be useful as prognostic and predictive markers. Recently, hypoxia-driven gene products have been launched as novel cancer treatment targets with the potential to increase tumour-specific effects. Breast cancer consists of a multitude of different diseases with certain common characteristics, but also clearly disparate behaviours and genetic alterations. In this review we will summarise the role of hypoxia in breast cancer and specifically outline the importance of hypoxia and HIF-1alpha regarding prognostic and treatment-specific implications. (Part of a Multi-author Review).     

Altered proteoglycan gene expression and the tumor stroma

Tumor stroma is a specialized form of tissue that is associated with epithelial neoplasms. Recent evidence indicates that significant changes in proteoglycan content occur in the tumor stroma and that these alterations could support tumor progression and invasion as well as tumor growth. Our main hypothesis is that the generation of tumor stroma is under direct control of the neoplastic cells and that, via a feedback loop, altered proteoglycan gene expression would influence the behavior of tumor cells. In this review, we will focus primarily on the work from our laboratory related to the altered expression of chondroitin sulfate proteoglycan and its role in tumor development and progression. The connective tissue stroma of human colon cancer is enriched in chondroitin sulfate and the stromal cell elements, primarily colon fibroblasts and smooth muscle cells, are responsible for this biosynthetic increase. These changes can be reproduced in vitro by using either tumor metabolites or co-cultures of human colon carcinoma cells and colon mesenchymal cells. The levels of decorin, a leucine-rich proteoglycan involved in the regulation of matrix assembly and cell proliferation, are markedly elevated in the stroma of colon carcinoma. These changes correlate with a marked increase in decorin mRNA levels and a concurrent hypomethylation of decorin gene, a DNA alteration associated with enhanced gene expression. Elucidation of decorin gene structure has revealed an unexpected degree of complexity in the 5 untranslated region of the gene with two leader exons that are alternatively spliced to the second coding exon. Furthermore, a transforming growth factor beta (TGF-)-negative element is present in the promoter region of decorin gene. This regulatory domain is likely to be implicated in the silencing of decorin gene by TGF- and may contribute to the regulation of this matrix gene in the tumor stroma.     

Interaction of epidermal growth factor with human fibroblasts in culture: an autoradiographic study at the ultrastructural level]

The potent mitogen epidermal growth factor (EGF) binds to specific receptors on human fibroblasts. In the present study we have used a quantitative EM autoradiographic approach to visualize the events involved in the binding process. When 125I-EGF is incubated at 4 degrees C for 120 min, labeled EGF primarily localizes to the plasma membrane of the fibroblast but when incubated at 37 degrees C for 120 min., over 2/3 of the labeled material is internalized by the cell. The internalized radioacitivity is primarily localized to lysomes. These studies demonstrate a temperature-dependent internalization of EGF following initial binding to specific plasma membrane receptors.     

The predictive value of temporally disaggregated volatility: evidence from index futures markets

This paper examines the benefits to forecasters of decomposing close-to-close return volatility into close-to-open (nighttime) and open-to-close (daytime) return volatility. Specifically, we consider whether close-to-close volatility forecasts based on the former type of (temporally aggregated) data are less accurate than corresponding forecasts based on the latter (temporally disaggregated) data. Results obtained from seven different US index futures markets reveal that significant increases in forecast accuracy are possible when using temporally disaggregated volatility data. This result is primarily driven by the fact that forecasts based on such data can be updated as more information becomes available (e.g., information flow from the preceding close-to-open/nighttime trading session). Finally, we demonstrate that the main findings of this paper are robust to the index futures market considered, the way in which return volatility is constructed, and the method used to assess forecast accuracy. Copyright © 2008 John Wiley & Sons, Ltd.     

RANKL,RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases

1997 saw the identification of a novel set of proteins within the tumor necrosis factor (TNF)/TNF receptor families that are required for the control of bone remodeling. Therefore, these receptors, receptor activator of nuclear factor kappa B (RANK), osteoprotegerin (OPG) and their ligand RANK ligand (RANKL) became the critical molecular triad controlling osteoclastogenesis and pathophysiologic bone remodeling. However, the establishment of the corresponding knock-out and transgenic mice revealed unexpected results, most particularly, the involvement of these factors in the vascular system and immunity. Thus, the OPG/RANK/RANKL molecular triad appears to be associated with vascular calcifications and plays a pivotal function in the development of the immune system through dendritic cells. OPG/RANK/RANKL thus constitute a molecular bridge spanning bone metabolism, vascular biology and immunity. This review summarizes recent knowledge of OPG/RANK/RANKL interactions and activities as well as the current evidence for their participation in osteoimmunology and vascular diseases. In fine, the targeting of the OPG/RANK/RANKL axis as novel therapeutic approaches will be discussed. Received 27 February 2007; accepted 4 April 2007     

Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury

Stroke and neurotrauma mediate neuronal death through a series of events that involve multiple interdependent molecular pathways. It has been suggested that these pathways are triggered following elevations in extracellular excitatory amino acids, primarily glutamate [1]. This report outlines mechanisms involving glutamate-mediated excitotoxicity with specific focus on (i) the role of Ca²⁺ in neurotoxicity, (ii) The concept of source specificity of neurotoxicity, (iii) the role of the ionotropic N-methyl-D-aspartate (NMDA)-subtype glutamate receptor and its associated submembrane molecules that may give rise to signaling specificity in excitotoxicity and (iv) the role of glutamate-mediated free-radical generation and associated cell death pathways. We also highlight a novel, peptide-based approach for uncoupling NMDA receptors from excitotoxicity in the rat central nervous system subjected to focal ischemia, thereby reducing stroke infarct volume and improving neurological functioning.Received 11 August 2003; received after revision 15 September 2003; accepted 17 September 2003     

Receptor binding, internalization, and retrograde transport of neurotrophic factors

This review deals with the receptor interactions of neurotrophic factors, focusing on the neurotrophins of the nerve growth factor (NGF) family, the glial cell derived neurotrophic factor (GDNF) family, and the ciliary neurotrophic factor (CNTF) family. The finding that two proteins, p75^NTR and Trk, act as receptors for NGF in neurons generated the discovery of other neurotrophic factors/receptor families and has enhanced our understanding of the development, survival, regeneration, and degeneration of the nervous system. The kinetics of binding, the structure of the ligand-receptor complex, and the mechanism of retrograde transport of the neurotrophins are discussed in detail and compared to information available on the GDNF and CNTF families. Each neurotrophic factor family, i.e., NGF, GDNF, and CNTF, has a set of receptors with specificity for individual members of the family and a common receptor without member specificity that, in some families, generates the cellular signal and retrograde transport.     

Fibroblast growth factor 21: an overview from a clinical perspective

Fibroblast growth factor 21 (FGF21) has been proposed as a novel putative therapeutic agent in type 2 diabetes. A large amount of data, predominantly obtained from murine models but also from non-human primates, suggest that FGF21 ameliorates obesity-associated hyperglycemia and hyperlipidemia primarily via effects on adipose tissue and the pancreas. In addition, FGF21 has been reported to play a pivotal regulatory role in starvation and ketosis. However, while it is clear that FGF21 has potent effects in vivo in several animal models, the exact mechanisms remain elusive. Moreover, very recent results from different human cohort studies have shown a paradoxical regulation of plasma FGF21 in obesity and type 2 diabetes as well as other important qualitative differences in the effects and regulation of FGF21 between rodents and humans. This review focuses on the most recently published data on FGF21 with emphasis on results obtained in humans.     

The effects of physostigmine on the oxygen uptake in rat brain tissue

Summary Physostigmine in a dose of 0.1 mg/kg i.v. expressly stimulated the oxygen uptake in the rat cerebral cortex. This effect was blocked by propranolol and seems be mediated by catecholamines. Since atropine also antagonized the stimulant effect of physostigmine, it appears that the action of physostigmine is primarily cholinergic and that the adrenergic effect is a secondary phenomenon. The higher dose of physostigmine (0.4 mg/kg i.v.) caused a depression of rat brain oxygen uptake.This work was supported by a grant from Serbian Republic Scientific Fund (ZMNU SR Srbija), Belgrade (Yugoslavia).The authors wish to acknowledge the skilful technical assistance of Lj. Krsti.     

Pancreatic polypeptide: A possible role in the regulation of food intake in the mouse. Hypothesis

Summary Pancreatic polypeptide (PP) is a recently identified hormone produced by pancreatic endocrine cells. The islets of genetically obese mice (ob/ob, C57 BL/6J), which are suspected to lack a circulating satiety factor, contain relatively few of the PP-producing cells. Administration of bovine pancreatic polypeptide (bPP) reduces food intake and suppresses body weight gain in the hyperphagic obese mice. It is postulated that PP participates in the regulation of food intake in a manner as yet undefined.This work was supported by grant No. 3.553.75 from Swiss National Science Foundation. We thank Mrs M. Eissler and Mr R. Cuche for their valuable help.     

Rheumatoid Arthritis and Interleukin-32

The inflammatory cytokine cascade plays a pivotal role in the pathogenesis of rheumatoid arthritis. Recently, a novel human cytokine, interleukin-32, was reported to induce tumor necrosis factor (TNF)-alpha. Interleukin-32 is expressed primarily in lymphoid tissues and leukocytes, but also in stimulated epithelial cells and synovial fibroblasts. Although the interleukin-32 receptor has not been reported, interleukin-32 can induce other inflammatory cytokines such as TNF-alpha, interleukin-1beta, and interleukin-6 from monocytes/macrophages in vitro and in vivo, and it synergizes with signals from pattern-recognition receptors. Notably, in the inflamed synovial tissues from rheumatoid arthritis patients, interleukin-32 is prominently expressed and correlates with the severity of arthritis and the expression of other cytokines, including TNF-alpha and interleukin-1. In experimental mice models of arthritis, joint injection of interleukin-32 induces joint inflammation, and overexpression of interleukin-32beta in hematopoietic cells exacerbates collagen-induced arthritis. Interleukin-32 can thus be seen to play an important role in the pathogenesis of rheumatoid arthritis.     

The effects of physostigmine on the oxygen uptake in rat brain tissue.

Physostigmine in a dose of 0.1 mg/kg i.v. expressly stimulated the oxygen uptake in the rat cerebral cortex. This effect was blocked by propranolol and seems be mediated by catecholamines. Since atropine also antagonized the stimulant effect of physostigmine, it appears that the action of physostigmine is primarily cholinergic and that the adrenergic effect is a secondary phenomenon. The higher dose of physostigmine (0.4 mg/kg i.v.) caused a depression of rat brain oxygen uptake.