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Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis.
Hendrix AS, Spoonmore TJ, Wilde AD, Putnam NE, Hammer ND, Snyder DJ, Guelcher SA, Skaar EP, Cassat JE
(2016) Antimicrob Agents Chemother 60: 5322-30
MeSH Terms: Animals, Anti-Bacterial Agents, Anti-Inflammatory Agents, Non-Steroidal, Bacterial Proteins, Bone Density Conservation Agents, Cell Survival, Delayed-Action Preparations, Diflunisal, Drug Repositioning, Female, Gene Expression, Humans, Mice, Mice, Inbred C57BL, Osteoblasts, Osteomyelitis, Primary Cell Culture, Staphylococcal Infections, Staphylococcus aureus, Trans-Activators, Treatment Outcome
Show Abstract · Added April 8, 2017
Staphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro Moreover, local delivery of diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo Collectively, these data demonstrate that diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
0 Communities
3 Members
0 Resources
21 MeSH Terms
Raloxifene improves skeletal properties in an animal model of cystic chronic kidney disease.
Newman CL, Creecy A, Granke M, Nyman JS, Tian N, Hammond MA, Wallace JM, Brown DM, Chen N, Moe SM, Allen MR
(2016) Kidney Int 89: 95-104
MeSH Terms: Animals, Blood Urea Nitrogen, Bone Density Conservation Agents, Bone Remodeling, Collagen, Disease Models, Animal, Femur, Male, Mechanical Phenomena, Parathyroid Hormone, Polycystic Kidney, Autosomal Dominant, Raloxifene Hydrochloride, Rats, Renal Insufficiency, Chronic, Spine
Show Abstract · Added November 23, 2015
Patients with chronic kidney disease (CKD) have an increased risk of fracture. Raloxifene is a mild antiresorptive agent that reduces fracture risk in the general population. Here we assessed the impact of raloxifene on the skeletal properties of animals with progressive CKD. Male Cy/+ rats that develop autosomal dominant cystic kidney disease were treated with either vehicle or raloxifene for five weeks. They were assessed for changes in mineral metabolism and skeletal parameters (microCT, histology, whole-bone mechanics, and material properties). Their normal littermates served as controls. Animals with CKD had significantly higher parathyroid hormone levels compared with normal controls, as well as inferior structural and mechanical skeletal properties. Raloxifene treatment resulted in lower bone remodeling rates and higher cancellous bone volume in the rats with CKD. Although it had little effect on cortical bone geometry, it resulted in higher energy to fracture and modulus of toughness values than vehicle-treated rats with CKD, achieving levels equivalent to normal controls. Animals treated with raloxifene had superior tissue-level mechanical properties as assessed by nanoindentation, and higher collagen D-periodic spacing as assessed by atomic force microscopy. Thus, raloxifene can positively impact whole-bone mechanical properties in CKD through its impact on skeletal material properties.
Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
1 Communities
2 Members
0 Resources
15 MeSH Terms
Bisphosphonates: from softening water to treating PXE.
Moore SN, Tanner SB, Schoenecker JG
(2015) Cell Cycle 14: 1354-5
MeSH Terms: ATP-Binding Cassette Transporters, Alendronate, Animals, Bone Density Conservation Agents, Etidronic Acid, Female, Humans, Male, Pseudoxanthoma Elasticum, Vascular Calcification
Added February 22, 2016
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1 Members
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10 MeSH Terms
Addressing the controversy: do bisphosphonates directly affect primary tumors?
Sterling JA
(2015) Cancer Discov 5: 14-5
MeSH Terms: Animals, Bone Density Conservation Agents, Diphosphonates, Female, Humans, Macrophages, Neoplasms, Tomography, Emission-Computed, Single-Photon, Tomography, X-Ray Computed
Show Abstract · Added February 12, 2015
The recent article by Junankar and colleagues focuses on demonstrating the uptake of bisphosphonates (BP) into the primary tumor in both animal models and human samples. Interestingly, the authors were able to establish tumor-associated macrophages as the cell type that takes up the BPs. These studies are an important advancement for understanding the potential benefits of using BPs as adjuvant therapy in patients with cancer.
©2015 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
9 MeSH Terms
Clinician's Guide to Prevention and Treatment of Osteoporosis.
Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R, National Osteoporosis Foundation
(2014) Osteoporos Int 25: 2359-81
MeSH Terms: Absorptiometry, Photon, Aged, Bone Density, Bone Density Conservation Agents, Calcium, Dietary, Diet, Female, Humans, Male, Middle Aged, Osteoporosis, Osteoporotic Fractures, Risk Assessment, Risk Factors, Spinal Fractures, Vitamin D
Show Abstract · Added January 20, 2015
The Clinician's Guide to Prevention and Treatment of Osteoporosis was developed by an expert committee of the National Osteoporosis Foundation (NOF) in collaboration with a multispecialty council of medical experts in the field of bone health convened by NOF. Readers are urged to consult current prescribing information on any drug, device, or procedure discussed in this publication.
0 Communities
1 Members
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16 MeSH Terms
Identification of myeloid cell subsets in murine lungs using flow cytometry.
Zaynagetdinov R, Sherrill TP, Kendall PL, Segal BH, Weller KP, Tighe RM, Blackwell TS
(2013) Am J Respir Cell Mol Biol 49: 180-9
MeSH Terms: Animals, Bone Density Conservation Agents, Clodronic Acid, Dendritic Cells, Flow Cytometry, Histocompatibility Antigens Class II, Lung, Macrophage Activation, Macrophages, Alveolar, Mice, Mice, Transgenic, Monocytes
Show Abstract · Added November 14, 2013
Although the antibody-based recognition of cell-surface markers has been widely used for the identification of immune cells, overlap in the expression of markers by different cell types and the inconsistent use of antibody panels have resulted in a lack of clearly defined signatures for myeloid cell subsets. We developed a 10-fluorochrome flow cytometry panel for the identification and quantitation of myeloid cells in the lungs, including pulmonary monocytes, myeloid dendritic cells, alveolar and interstitial macrophages, and neutrophils. After the initial sorting of viable CD45(+) leukocytes, we detected three leukocyte subpopulations based on CD68 expression: CD68(-), CD68(low), and CD68(hi). Further characterization of the CD68(hi) population revealed CD45(+)/CD68(hi)/F4/80(+)/CD11b(-)/CD11c(+)/Gr1(-) alveolar macrophages and CD45(+)/CD68(hi)/F4/80(-)/CD11c(+)/Gr1(-)/CD103(+)/major histocompatibility complex (MHC) class II(hi) dendritic cells. The CD68(low) population contained primarily CD45(+)/CD68(low)/F4/80(+)/CD11b(+)/CD11c(+)/Gr1(-)/CD14(low) interstitial macrophages and CD45(+)/CD68(low)/F4/80(+)/CD11b(+)/CD11c(-)/Gr1(low)/CD14(hi) monocytes, whereas the CD68(-) population contained neutrophils (CD45(+)/CD68(-)/F4/80(-)/CD11b(+)/Gr1(hi)). The validity of cellular signatures was confirmed by a morphological analysis of FACS-sorted cells, functional studies, and the depletion of specific macrophage subpopulations using liposomal clodronate. We believe our approach provides an accurate and reproducible method for the isolation, quantification, and characterization of myeloid cell subsets in the lungs, which may be useful for studying the roles of myeloid cells during various pathological processes.
2 Communities
3 Members
0 Resources
12 MeSH Terms
Complex regional pain syndrome: practical diagnostic and treatment guidelines, 4th edition.
Harden RN, Oaklander AL, Burton AW, Perez RS, Richardson K, Swan M, Barthel J, Costa B, Graciosa JR, Bruehl S, Reflex Sympathetic Dystrophy Syndrome Association
(2013) Pain Med 14: 180-229
MeSH Terms: Adrenergic alpha-Agonists, Analgesics, Opioid, Anesthetics, Local, Anti-Inflammatory Agents, Anticonvulsants, Antidepressive Agents, Tricyclic, Bone Density Conservation Agents, Complex Regional Pain Syndromes, Humans, Occupational Therapy, Physical Therapy Modalities, Receptors, N-Methyl-D-Aspartate, Recreation Therapy, Reflex Sympathetic Dystrophy, Rehabilitation, Vocational
Show Abstract · Added May 20, 2014
OBJECTIVE - This is the fourth edition of diagnostic and treatment guidelines for complex regional pain syndrome (CRPS; aka reflex sympathetic dystrophy).
METHODS - Expert practitioners in each discipline traditionally utilized in the treatment of CRPS systematically reviewed the available and relevant literature; due to the paucity of levels 1 and 2 studies, less rigorous, preliminary research reports were included. The literature review was supplemented with knowledge gained from extensive empirical clinical experience, particularly in areas where high-quality evidence to guide therapy is lacking.
RESULTS - The research quality, clinical relevance, and "state of the art" of diagnostic criteria or treatment modalities are discussed, sometimes in considerable detail with an eye to the expert practitioner in each therapeutic area. Levels of evidence are mentioned when available, so that the practitioner can better assess and analyze the modality under discussion, and if desired, to personally consider the citations. Tables provide details on characteristics of studies in different subject domains described in the literature.
CONCLUSIONS - In the humanitarian spirit of making the most of all current thinking in the area, balanced by a careful case-by-case analysis of the risk/cost vs benefit analysis, the authors offer these "practical" guidelines.
Wiley Periodicals, Inc.
0 Communities
1 Members
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15 MeSH Terms
Duration of treatment in postmenopausal osteoporosis: how long to treat and what are the consequences of cessation of treatment?
Laster AJ, Tanner SB
(2011) Rheum Dis Clin North Am 37: 323-36, v
MeSH Terms: Bone Density Conservation Agents, Bone and Bones, Estrogen Replacement Therapy, Female, Fractures, Bone, Humans, Middle Aged, Osteoporosis, Postmenopausal, Practice Guidelines as Topic, Risk Factors, Substance Withdrawal Syndrome
Show Abstract · Added January 20, 2015
Although a variety of medications are effective for the treatment of postmenopausal osteoporosis, there is concern that long-term use may incur side effects. Consequently, some have proposed discontinuing or temporarily suspending treatment after a defined period of time. As the benefits of fracture risk reduction may recede during this "drug holiday", the clinician may be faced with deciding when to resume therapy (and with which agent) while avoiding the possible cumulative risk of side effects. This article summarizes data regarding length of treatment and the effects of cessation of treatment on bone density, bone turnover markers, and fracture risk.
Copyright © 2011 Elsevier Inc. All rights reserved.
0 Communities
1 Members
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11 MeSH Terms
Bone structural components regulating sites of tumor metastasis.
Sterling JA, Guelcher SA
(2011) Curr Osteoporos Rep 9: 89-95
MeSH Terms: Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Bone Density Conservation Agents, Bone Neoplasms, Breast Neoplasms, Denosumab, Diphosphonates, Female, Humans, Kruppel-Like Transcription Factors, Male, Nuclear Proteins, Parathyroid Hormone-Related Protein, RANK Ligand, Transforming Growth Factor beta, Zinc Finger Protein Gli2, rho-Associated Kinases
Show Abstract · Added March 5, 2014
Tumors such as breast, lung, and prostate frequently metastasize to bone, where they can cause intractable pain and increase the risk of fracture in patients. When tumor cells metastasize to bone, they interact with the microenvironment to promote bone destruction primarily through the secretion of osteolytic factors by the tumor cells and the subsequent release of growth factors from the bone. Our recent data suggest that the differential rigidity of the mineralized bone microenvironment relative to that of soft tissue regulates the expression of osteolytic factors by the tumor cells. The concept that matrix rigidity regulates tumor growth is well established in solid breast tumors, where increased rigidity stimulates tumor cell invasion and metastasis. Our studies have indicated that a transforming growth factor-β (TGF-β) and Rho-associated kinase (ROCK)-dependent mechanism is involved in the response of metastatic tumor cells to the rigid mineralized bone matrix. In this review, we will discuss the interactions between ROCK and TGF-β signaling, as well as potential new therapies that target these pathways.
1 Communities
2 Members
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17 MeSH Terms
Drugs which inhibit osteoclast function suppress tumor growth through calcium reduction in bone.
Li X, Liao J, Park SI, Koh AJ, Sadler WD, Pienta KJ, Rosol TJ, McCauley LK
(2011) Bone 48: 1354-61
MeSH Terms: Animals, Bone Density Conservation Agents, Bone and Bones, Calcium, Cell Division, Cell Line, Tumor, Diphosphonates, Dogs, Imidazoles, Male, Mice, Mice, Nude, Osteoclasts, Prostatic Neoplasms, Zoledronic Acid
Show Abstract · Added March 5, 2014
Prostate carcinoma frequently metastasizes to bone where the microenvironment facilitates its growth. Inhibition of bone resorption is effective in reducing tumor burden and bone destruction in prostate cancer. However, whether drugs that inhibit osteoclast function inhibit tumor growth independent of inhibition of bone resorption is unclear. Calcium is released during bone resorption and the calcium sensing receptor is an important regulator of cancer cell proliferation. The goal of this investigation was to elucidate the role of calcium released during bone resorption and to determine the impact of drugs which suppress bone resorption on tumor growth in bone. To compare tumor growth in a skeletal versus non-skeletal site, equal numbers of canine prostate cancer cells expressing luciferase (ACE-1(luc)) were inoculated into a simple collagen matrix, neonatal mouse vertebrae (vossicles), human de-proteinized bone, or a mineralized collagen matrix. Implants were placed subcutaneously into athymic mice. Luciferase activity was used to track tumor growth weekly, and at one month tumors were dissected for histologic analysis. Luciferase activity and tumor size were greater in vossicles, de-proteinized bone and mineralized collagen matrix versus non-mineralized collagen implants. The human osteoblastic prostate carcinoma cell line C4-2b also grew better in a mineral rich environment with a greater proliferation of C4-2b cells reflected by Ki-67 staining. Zoledronic acid (ZA), a bisphosphonate, and recombinant OPG-Fc, a RANKL inhibitor, were administered to mice bearing vertebral implants (vossicles) containing ACE-1 osteoblastic prostate cancer cells. Vossicles or collagen matrices were seeded with ACE-1(luc) cells subcutaneously in athymic mice (2 vossicles, 2 collagen implants/mouse). Mice received ZA (5 μg/mouse, twice/week), (OPG-Fc at 10mg/kg, 3 times/week) or vehicle, and luciferase activity was measured weekly. Histologic analysis of the tumors, vossicles and endogenous bones and serum biochemistry were performed. Antiresorptive administration was associated with decreased serum TRAP5b, reduced osteoclast numbers, and increased tibia and vossicle bone areas. ZA significantly decreased bone marrow calcium concentrations without affecting serum calcium. ZA and OPG-Fc significantly inhibited tumor growth in bone but not in collagen implants. In conclusion, the inhibitory effects of ZA or OPG-Fc on prostate tumor growth in bone are mediated via blocking bone resorption and calcium release from bone.
Copyright © 2011 Elsevier Inc. All rights reserved.
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1 Members
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15 MeSH Terms