Publications by authors named "Mark Nanes"

Disseminated cryptococcosis infection typically occurs in immunocompromised patients, often through pneumonia or meningoencephalitis. Cases in immunocompetent patients are uncommon, and presentation in either bone or adrenal glands are rare. We describe a case of a previously healthy immunocompetent 50-year-old woman who presented with lytic bone lesions followed by meningoencephalitis, dermatologic involvement, and adrenal insufficiency from disseminated cryptococcus.

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Purpose Of Review: The aim of this study is to summarize monitoring, prevention and treatment options of glucocorticoid-induced osteoporosis for patients on chronic glucocorticoid therapy.

Recent Findings: Recent meta-analyses highlight the efficacy of bisphosphonate use in improving bone mineral density and in reducing vertebral fractures in the setting of long-term glucocorticoid use. A new study has now shown that alendronate also reduces the risk of hip fracture in glucocorticoid use.

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Basal phenotype breast cancer is one of the most aggressive breast cancers that frequently metastasize to brain. The role of sex hormones and their receptors in development of this disease is largely unclear. We demonstrated that mPRα was expressed at a moderate level in a brain metastatic BPBC cell line MB231Br, which was derived from the parent mPRα undetectable MB231 cells.

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Osteoporosis.

Semin Nucl Med

June 2015

Osteoporotic fractures are common and result in extensive morbidity and mortality. It is possible to decrease the risk of fracture in postmenopausal, male, and glucocorticoid-induced osteoporosis with appropriate screening and treatment. The assessment of fracture risk, for which bone densitometry is only 1 component, should be the main focus of patient evaluation.

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Phosphate wasting and fibroblast growth factor-23.

Curr Opin Endocrinol Diabetes Obes

December 2013

Purpose Of Review: The purpose of this study is to review the regulation of phosphate and recent progress in fibroblast growth factor-23 (FGF-23), a key phosphate regulatory hormone.

Recent Findings: Phosphate is required for mineralization of bone, muscle strength and a host of biologic functions. Phosphate is sensed by bone that responds with secretion of FGF-23.

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The heterogeneous nuclear ribonucleoprotein (hnRNP)-like estrogen response element-binding protein (ERE-BP) competes with estrogen receptor α (ERα) for occupancy of estrogen response elements (EREs). Here we report that ERE-BP potently stimulates osteoclastogenesis. ERE-BP mRNA and protein were found to be expressed ubiquitously in bone.

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Introduction: Prevention of osteoporotic fractures is desirable to decrease morbidity, mortality and health care costs. The World Health Organization Fracture Assessment Tool (FRAX) enhances physician treatment decisions by combining epidemiologic fracture risk calculations with bone density. The authors sought to determine the effect of reporting FRAX results and treatment recommendations in bone density reports on clinician prescribing behavior.

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Tumor necrosis factor α (TNF-α) promotes bone loss and inhibits bone formation. Osterix (Osx, SP7) is a transcription factor required for osteoblast (OB) differentiation because deletion results in a cartilaginous skeleton. We previously described a TNF suppressor element in the Osx promoter that was used to isolate nuclear proteins mediating TNF inhibition of OB differentiation.

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NADPH oxidases are a major source of superoxide production in the vasculature. The constitutively active Nox4 subunit, which is selectively upregulated in the lungs of human subjects and experimental animals with pulmonary hypertension, is highly expressed in vascular wall cells. We demonstrated that rosiglitazone, a synthetic agonist of the peroxisome proliferator-activated receptor-γ (PPARγ), attenuated hypoxia-induced pulmonary hypertension, vascular remodeling, Nox4 induction, and reactive oxygen species generation in the mouse lung.

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Vitamin D is the critical hormone for intestinal absorption of calcium. Optimal calcium absorption is important for proper mineralization of bone in the prevention of osteoporosis and osteoporotic fractures, among other important functions. Diseases associated with gut inflammation, such as Crohn's disease (CD), may impair calcium absorption.

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Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis because it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here, we show that iPTH increases the production of Wnt10b by bone marrow CD8+ T cells and induces these lymphocytes to activate canonical Wnt signaling in preosteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in preosteoblasts and blunted osteoblastic commitment, proliferation, differentiation, and life span, which result in decreased trabecular bone anabolism and no increase in strength.

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Objective: To review the latest tools in the clinical assessment of fracture risk and to review new and emerging options for osteoporosis therapy.

Design: Retrospective analysis of published studies regarding the diagnosis and treatment of osteoporosis.

Result(s): Large-scale epidemiologic data were recently assembled by the World Health Organization to produce a Web-based clinical assessment tool, FRAX, which uses clinical and historical data to provide prompt assessment and quantitation of fracture risk.

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Parathyroid hormone (PTH) binds to its receptor on osteoblasts to regulate gene transcription primarily through the elevation of the second messenger cAMP. A number of genes regulated by PTH in osteoblasts contain GC-rich and Sp-binding sites. Osterix (Osx, Sp7) is a transcription factor required for the differentiation of osteoblasts that can bind to Sp-binding sites on gene promoters and regulate their expression.

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Objective: To determine the efficacy and safety of commonly prescribed regimens for the treatment of vitamin D insufficiency.

Methods: We performed a retrospective analysis of 306 consecutive patients who were prescribed ergocalciferol (vitamin D2) for correction of vitamin D insufficiency at the Atlanta Veterans Affairs Medical Center between February 2003 and May 2006. Serum levels of parathyroid hormone, 25-hydroxyvitamin D (25-OHD), and calcium were compared before and after treatment with ergocalciferol.

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Transcription factors regulate tissue-specific differentiation of pluripotent mesenchyme to osteoblast (OB), myoblast (MB), and other lineages. Osterix (Osx) is an essential transcription factor for bone development because knockout results in lack of a mineralized skeleton. The proximal Osx promoter contains numerous binding sequences for MyoD and 14 repeats of a binding sequence for Myf5.

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Background: The prevalences of both hypertension and vitamin D insufficiency are high in the United States. Recent clinical trials and animal studies have suggested that vitamin D insufficiency may be associated with elevated blood pressure.

Objective: With cross-sectional data, we sought to determine whether vitamin D concentrations were related to systolic blood pressure (SBP) in the third National Health and Nutrition Examination Survey (1988-1992).

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Unlabelled: Endogenous TNFalpha prevents the attainment of maximum achievable peak bone mass in vivo. In vitro, TNFalpha suppresses BMP-2- and TGFbeta-mediated Smad activation through induction of NF-kappaB. Consistently, pharmacological suppression of NF-kappaB augments osteoblast differentiation and mineralization in vitro.

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Background: IGF-I is an important growth and differentiative factor for osteoblasts and may have a role in defining prostate cancer risk and skeletal metastases.

Methods: Conditioned media (CM) from human prostate cancer (PC), C4-2 and C4-2B, which produce osteoblastic lesions, and PC-3, which causes osteolysis, was added to MC3T3-E1 bone cultures. SCID mice were injected intratibially with these engineered cells.

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Mechanical strain inhibits osteoclastogenesis by regulating osteoblast functions: We have shown that strain inhibits receptor activator of NF-kappaB ligand (RANKL) expression and increases endothelial nitric oxide synthase (eNOS) and nitric oxide levels through ERK1/2 signaling in primary bone stromal cells. The primary stromal culture system, while contributing greatly to understanding of how the microenvironment regulates bone remodeling is limited in use for biochemical assays and studies of other osteoprogenitor cell responses to mechanical strain: Stromal cells proliferate poorly and lose aspects of the strain response after a relatively short time in culture. In this study, we used the established mouse osteoblast cell line, conditionally immortalized murine calvarial (CIMC-4), harvested from mouse calvariae conditionally immortalized by insertion of the gene coding for a temperature-sensitive mutant of SV40 large T antigen (TAg) and support osteoclastogenesis.

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Osteoblast (OB) differentiation is suppressed by tumor necrosis factor-alpha (TNF-alpha), an inflammatory stimulus that is elevated in arthritis and menopause. Because OB differentiation requires the expression of the transcription factor osterix (Osx), we investigated TNF effects on Osx. TNF inhibited Osx mRNA in pre-osteoblastic cells without affecting Osx mRNA half-life.

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Mechanical input is known to regulate bone remodeling, yet the molecular events involved in mechanical signal transduction are poorly understood. We here investigate proximal events leading to the ERK1/2 activation that is required for mechanical repression of RANKL (receptor activator of NF-kappaB ligand) expression, the factor that controls local recruitment of osteoclasts. Using primary murine bone stromal cells we show that dynamic mechanical strain via substrate deformation activates Ras-GTPase, in particular the H-Ras isoform.

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After menopause, increased tumor necrosis factor-alpha (TNF-alpha) stimulates bone resorption while inhibiting differentiation of new bone-forming osteoblasts (OB). TNF receptors, p55 and p75, signal similar intracellular pathways, but only p55 activates apoptosis. To evaluate the relationship between the TNF receptor mediating inhibition of OB differentiation and the role of apoptosis, marrow stromal cells (MSC) were cultured from mice deficient in either or both receptors.

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Receptor activator of NFkappa-B ligand (RANKL) is essential for osteoclast formation, function, and survival. Although RANKL mRNA and protein levels are modulated by 1,25(OH)2D3 and other osteoactive factors, regulatory mechanisms remain unclear. In this study, we show that 2 kb or 2 kb plus exon 1 of a RANKL promoter sequence conferred neither 1,25(OH)2D3 response nor tissue specificity.

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Resistance to the action of vitamin D (D) occurs in response to tumor necrosis factor-alpha (TNF-alpha), an effect mediated by nuclear factor kappa B (NfkappaB). To determine the mechanism of NfkappaB inhibition of D-stimulated transcription, chromatin immunoprecipitation assays (CHIP) were done in osteoblastic ROS 17/2.8 cells that had been treated with TNF-alpha or transfected with the p65 subunit of NfkappaB.

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