Current Pharmaceutical Design - Volume 10, Issue 21, 2004
Volume 10, Issue 21, 2004
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Osteoblast Differentiation and Control by Vitamin D and Vitamin D Metabolites
Authors: M. Driel van, H. A.P. Pols and J.P. T.M. van LeeuwenVitamin D plays a major role in the regulation of mineral homeostasis and affects bone metabolism. Most effects of vitamin D have been attributed to the 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) metabolite. 1,25-(OH)2D3 regulates its own metabolism by mediating the 24-hydroxylase activity, which leads to the degradation of the molecule but intermediate products (24-hydroxylated forms of 25-(OH)D3 and 1,25-(OH)2D3) may be biologically active too. In this review we describe the direct effects of 1,25-(OH)2D3 on osteoblast function (proliferation, apoptosis, expression of specific bone proteins and growth factors) and mineralization. The role of the vitamin D receptor, vitamin D metabolism and the effects on osteoblast gene expression are documented. Vitamin D acts often in interaction with factors. The effects of 1,25-(OH)2D3 on the expression of growth factors and its interaction with growth factors and hormones in the control of osteoblast differentiation are discussed. Finally, the current status of the development of synthetic vitamin D analogs with bone anabolic characteristics for therapeutic application is described.
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Retracted: Effects of Vitamin K2 on Osteoporosis
Authors: Jun Iwamoto, Tsuyoshi Takeda and Yoshihiro SatoThe article entitled “Effects of Vitamin K2 on Osteoporosis, published in Curr Pharm Des 2004; 10(21): 2557-76, by Iwamoto J, Takeda T and Sato Y.” has been retracted by the Editorial office of the journal Current Pharmaceutical Design, as the text, data and some figures used/referred in this review article are from sources which have been retracted or under investigation on the basis of data fabrication and falsification, authorship misconduct, duplicate publication, unethical research practices, text recycling/self-plagiarism, and unresolved concerns about data integrity and research conduct. The authors were informed of this complaint and were requested to give justification on the matter in their defense. However, no reply was received from their side in this regard. Some sources that have been retracted are as follows: 1. Iwamoto J, Takeda T, Ichimura S. Combined treatment with vitamin K2 and bisphosphonate in postmenopausal women with osteoporosis. Yonsei Med J 2003; 44: 751-6. Available at: https://eymj.org/DOIx.php?id=10.3349/ymj.2019.60.1.115. 2. Sato Y, Honda Y, Kuno H, Oizumi K. Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients. Bone 1998; 23: 291-6. Available at: https://www.sciencedirect.com/science/article/pii/S8756328298001082. 3. Sato Y, Honda Y, Kaji M, Asoh T, Hosokawa K, Kondo I, et al. Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency. Bone 2002; 31: 114-8. Available at: https://pubmed.ncbi.nlm.nih.gov/ 12110423/. Bentham Science apologizes to its readers for any inconvenience this may have caused. The Bentham Editorial Policy on Article Retraction can be found at https://benthamscience.com/editorial-policies-main.php Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.
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The Anabolic Effects of GH/IGF System on Bone
Authors: Yuji Kasukawa, Naohisa Miyakoshi and Subburaman MohanOsteoporosis is the result of imbalance in bone remodeling caused by increased bone resorption and decreased bone formation. In terms of the mechanisms for the age-related impairment in bone formation, a deficiency in growth hormone (GH) / insulin-like growth factor (IGF) system that occurs with age has been proposed to play a major role. The potential causes for age-related decline in GH secretion are under active investigation and may involve multiple mechanisms including GH secretagogues, sex hormones, nutritional status and physical activity. Although a number of animal and clinical studies have provided experimental evidence for potential use of GH / IGF system components to increase bone mass, the clinical utility of GH / IGF system components for treatment of osteoporosis has not come to fruition because of our incomplete understanding of the regulation of production and actions of GH / IGF system components. Regarding the actions of GH in target tissues, there is evidence that IGF system plays a major role in mediating the GH effects. In addition, GH may also exert effects on certain target tissues independent of IGFs. It is also known that GH effects on target tissue involve multiple components of the IGF system including the ligands, receptors, IGF binding proteins (IGFBP), IGFBP proteases and activators and inhibitors of IGFBP proteases. Future studies on the mechanisms that contribute to age-related impairment in GH / IGF axis and the molecular pathways that contribute to the bone forming effects of GH / IGF axis may provide a foundation for the development of safe and effective therapies involving one or more IGF system components to correct bone formation deficit in the elderly subjects.
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Growth Factors and Bone Formation in Osteoporosis: Roles for Fibroblast Growth Factor and Transforming Growth Factor Beta
Authors: Olivia Fromigué, Dominique Modrowski and Pierre J. MarieOsteoporosis is characterised by excess bone fragility resulting from bone loss and altered bone microarchitecture. Bone loss occurring during aging and after menopause in women is known to result from an imbalance between bone formation and resorption. Bone formation is dependent on the commitment of osteoprogenitor cells, the proliferation of pre-osteoblasts, their differentiation into mature osteoblasts synthesising bone matrix and the life-span of mature osteoblasts. Transforming Growth Factor ß (TGFß) and Fibroblast Growth Factors (FGFs) are important factors that promote osteoprogenitor cell proliferation and osteogenesis. Reduced expression of TGFß in bone was found in several animal models of osteopenia. In addition, both FGF and TGFß were found to exert anabolic effects on bone formation in intact animals and to reduce bone loss in experimental models of osteoporosis. Both genetic manipulation of FGF and TGFß or their receptors in mice and bone phenotype associated with FGF receptors and TGFß mutations or polymorphism suggest that TGFß and FGF signalling may contribute to the control of osteogenesis and bone mass in vivo. The determination of molecular mechanisms involved in the anabolic actions of FGF and TGFß in cells of the osteoblastic lineage may lead in the future to the development of new therapeutic strategies aimed at improving bone formation in osteoporotic patients.
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Osteoporosis Requires Bone-Specific Statins
Authors: Masao Koida, Ryo Fukuyama and Hiromichi NakamutaRemedies for primary osteoporosis are increasing in brands but not always with concomitant improvements in efficacy and safety. Clinical studies suggest that nitrogen-containing bisphosphonates alone display sufficient practical effectiveness to survive as effective therapy. However, their less effectiveness in highly osteopenic patients due to their lack of genuine bone anabolic effect waits improvements. Pinpointing statins as the inducer of BMP-2 provoked a rush of clinical and laboratory studies to identify bone anabolic properties. Clinical studies, even if only through observational, suggest that under conventional dosing conditions for hyperlipemia, the liver-targeted statins now in use display insufficient bone anabolic effect, although laboratory studies seem to be clarifying the mechanisms underlying intrinsic bone anabolic properties. While incomplete, these studies indicate the possibility that, if bioavailability to bone could be improved by simply changing dosing methods and/or deliberate derivatization, the genuine anabolic properties of statins on bone could be extracted and put into therapeutic use.
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Effects of Parathyroid Hormone on Cancellous Bone Mass and Structure in Osteoporosis
More LessParathyroid hormone (PTH) is the major hormonal regulator of calcium homeostasis. PTH is a potent stimulator of bone formation and can restore bone to an osteopenic skeleton, when administered intermittently. Osteoblasts are the primary target cells for the anabolic effects of PTH in bone tissue. Anabolic effects of PTH on bone have been demonstrated in animals and humans, by numerous measurement techniques including bone mineral density and bone histomorphometry. Clinically, the most important aspect of treatment for osteoporosis is prevention of fractures. Microstructural alterations, such as loss of trabecular connectivity, have been implicated in increased propensity for fracture. Recent two-dimensional (2D) and three-dimensional (3D) assessments of cancellous bone structure have shown that PTH can re-establish lost trabecular connectivity in animals and humans. These results provide new insight into the positive clinical effects of PTH in osteoporosis. In recent randomized controlled clinical trials of intermittent PTH treatment, PTH decreased incidence of vertebral and non-vertebral fractures in postmenopausal women. Thus, PTH shows strong potential as therapy for osteoporosis. However, 2D and 3D structural analysis of advanced osteopenia in animals has shown that there is a critical limit of trabecular connectivity and bone strength below which PTH cannot completely reverse the condition. Given that PTH treatment fails to completely restore trabecular connectivity and bone strength in animals with advanced osteopenia, early treatment of osteoporosis appears important and efficacious for preventing fractures caused by decreased bone strength resulting from decreased trabecular connectivity.
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Exercise as an Anabolic Stimulus for Bone
Authors: Charles H. Turner and Alexander G. RoblingMechanical loading provides an anabolic stimulus for bone. More importantly, the mechanosensing apparatus in bone directs osteogenesis to where it is most needed for improving bone strength. The biological processes involved in bone mechanotransduction are poorly understood and further investigation of the molecular mechanisms might uncover drug targets for osteoporosis. Several pathways are emerging from current research, including membrane ion channels, ATP signaling, and second messengers such as prostaglandins and nitric oxide. Some key molecular targets include the Ltype calcium channel (alpha 1C isoform), a gadolinium-sensitive stretch-activated channel, P2Y2 and P2X7 purinergic receptors, EP2 and EP4 prostanoid receptors, and the parathyroid hormone receptor. One characteristic of the mechanosensing apparatus that has only recently been studied is the important role of desensitization. Experimental protocols that insert “rest” periods to reduce the effects of desensitization can double anabolic responses to mechanical loading. A drug therapy that suppresses desensitization pathways may provide an effective means to build bone strength.
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Chloroquine and Hydroxychloroquine as Inhibitors of Human Immunodeficiency Virus (HIV-1) Activity
Authors: Frank Romanelli, Kelly M. Smith and Ardis D. HovenRecent advances in the development of antiretrovirals have significantly extended life-spans and positively impacted morbidity of HIV-seropositive patients. While effective, antiretrovirals are associated with complex medication regimens, large pill burdens, and significant side effects which may impact quality of life. Researchers continue to examine various chemical entities in their search for agents with anti-HIV activity. Ideal agents would be efficacious, easily dosed and administered, inexpensive, and with few adverse effects. Chloroquine and its analog hydroxychloroquine are two inexpensive agents that are widely used for the treatment of malaria and have been shown to achieve some level of anti-HIV activity. The exact mechanism of chloroquine and hydroxychloroquines anti-HIV activity has not yet been discerned but may be related to effects on HIVs surface envelope glycoprotein 120. If found efficacious, both drugs would offer significant advantages to current therapy including a unique mechanism of action, lack of cross-resistance with other antiretrovirals, and low cost. Early and limited in vitro and in vivo data have demonstrated modest anti-HIV efficacy as indicated by measures of viral burden. Effects on CD4+ cell counts have not been as pronounced. It is premature to advocate the use of either of these agents in the management of routine HIV disease; however; the drugs should be further studied to determine their benefit in the treatment of patients who have exhausted all standard treatments. Larger, well-controlled trials are needed to discern the potential role of chloroquine and hydroxychloroquine in the management of HIV.
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Testosterone Action on the Sertoli Cell Membrane: A KIR6.x Channel Related Effect
Authors: Wassermann G. F. and Loss E. S.This review focuses on the fast testosterone actions on the cell membrane principally on the Sertoli cells, its predominant effect, i.e. an increase in [Ca2+]i and the possibility of its actions being mediated by KIR (ATP) channels. The regulation of the K+ ATP channels by phosphatidylinositol-4,5-bisphosphate depletion on the cell membrane as a result of the action of testosterone, its putative receptors, and the phospholipase C - phosphatidylinositol-4,5-bisphosphate pathway are discussed. The electrostatic interaction between anionic and cationic charges on the K+ ATP modulation is also considered, in the light of testosterones effect on phospholipase C - phosphatidylinositol-4,5-bisphosphate hydrolysis. Thus, the interaction of testosterone with its putative receptors, phospholipase C, phosphatidylinositol-4,5-bisphosphate, and K+ ATP channels (or other KIR channels) in the membrane may be one of the mechanism of rapid testosterones physiological action on some classes of cells.
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Volumes & issues
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Volume 31 (2025)
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Volume (2025)
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)
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