In drug discovery and development, X-ray micro-computed tomography (micro-CT) has gained increasing importance over the past decades. In recent years, micro-CT imaging of soft tissues has become popular due to the introduction of a variety of radiopaque contrast agents. More recently, nanoparticle-based ExiTron nano 12,000 has become commercially available for the nonclinical micro-CT imaging of soft tissues in rodents.
View Article and Find Full Text PDFTanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice.
View Article and Find Full Text PDFMetabolic syndrome and osteoporosis share similar risk factors. Also, patients with diabetes have a higher risk of osteoporosis and fracture. Liver manifestations, such as non-alcoholic steatohepatitis (NASH), of metabolic syndrome are further aggravated in diabetics and often lead to liver failure.
View Article and Find Full Text PDFFibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1α,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft-tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway.
View Article and Find Full Text PDFObjective: To investigate whether the effects of nerve growth factor (NGF) inhibition with tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials.
Methods: Male Lewis rats underwent MMT surgery and were treated weekly with tanezumab (0.1, 1 or 10 mg/kg), isotype control or vehicle for 7, 14 or 28 days.
Introduction: Osteoarthritis (OA) is a leading cause of disability, but despite the high unmet clinical need and extensive research seeking dependable therapeutic interventions, no proven disease-modifying treatment for OA is currently available. Due to the close interaction and interplay between the articular cartilage and the subchondral bone plate, it has been hypothesized that antiresorptive drugs can also reduce cartilage degradation, inhibit excessive turnover of the subchondral bone plate, prevent osteophyte formation, and/or that bone anabolic drugs might also stimulate cartilage synthesis by chondrocytes and preserve cartilage integrity. The benefit of intensive zoledronate (Zol) and parathyroid hormone (PTH) therapy for bone and cartilage metabolism was evaluated in a rat model of OA.
View Article and Find Full Text PDFBackground: To acquire the most meaningful understanding of human arthritis, it is essential to select the disease model and methodology translatable to human conditions. The primary objective of this study was to evaluate a number of analytic techniques and biomarkers for their ability to accurately gauge bone and cartilage morphology and metabolism in the medial meniscal tear (MMT) model of osteoarthritis (OA).
Methods: MMT surgery was performed in rats to induce OA.
Orally administered small molecule agonists of soluble guanylate cyclase (sGC) induced increased numbers of osteoclasts, multifocal bone resorption, increased porosity, and new bone formation in the appendicular and axial skeleton of Sprague-Dawley rats. Similar histopathological bone changes were observed in both young (7- to 9-week-old) and aged (42- to 46-week-old) rats when dosed by oral gavage with 3 different heme-dependent sGC agonist (sGCa) compounds or 1 structurally distinct heme-independent sGCa compound. In a 7-day time course study in 7- to 9-week-old rats, bone changes were observed as early as 2 to 3 days following once daily compound administration.
View Article and Find Full Text PDFBone has a high potential for endogenous self-repair. However, due to population aging, human diseases with impaired bone regeneration are on the rise. Current strategies to facilitate bone healing include various biomolecules, cellular therapies, biomaterials and different combinations of these.
View Article and Find Full Text PDFBackground: Metastatic bladder cancer is a serious condition with a 5-year survival rate of approximately 14 %, a rate that has remained unchanged for almost three decades. Thus, there is a profound need to identify the driving mutations for these aggressive tumors to better determine appropriate treatments. Mutational analyses of clinical samples suggest that mutations in either the phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) or RAS/MEK/ERK pathways drive bladder cancer progression, although it remains to be tested whether the inhibition of either (or both) of these pathways can arrest PI3K/mTOR- or Ras-driven proliferation.
View Article and Find Full Text PDFObjective: Tumor recurrence and metastasis is the most common cause of mortality in hepatocellular carcinoma (HCC) patients. Despite positive results with vascular endothelial growth factor (VEGF) inhibitors in preclinical studies using HCC xenograft models, the clinical outcome in HCC patients has been disappointing. So far, only the multitargeted tyrosine kinase inhibitor sorafenib has been shown to significantly improve survival in HCC patients, suggesting that this class of agents could be effective against HCC.
View Article and Find Full Text PDFTo accommodate functional demands, the composition and organization of the skeleton differ among species. Microcomputed tomography has improved our ability markedly to assess structural parameters of cortical and cancellous bone. The current study describes differences in cortical and cancellous bone structure, bone mineral density, and morphology (geometry) at the proximal femur, proximal femoral diaphysis, lumbar vertebrae, and mandible in mice, rats, rabbits, dogs, and nonhuman primates.
View Article and Find Full Text PDFThe overwhelming need to improve preclinical models in oncology has stimulated research efforts to refine and validate robust orthotopic models that closely mimic the disease population and therefore have the potential to better predict clinical outcome with novel therapies. Sophisticated technologies including bioluminescence, contrast enhanced ultrasound imaging, positron emission tomography, computed tomography and magnetic resonance imaging have been added to existing serum- and histology-based biomarkers to assist with patient selection and the design of clinical trials. The rationale for the use of human hepatocellular carcinoma (HCC) cell lines, implementation of xenograft and orthotopic animal models and utilization of available biomarkers have been discussed, providing guidelines to facilitate preclinical research for the development of treatments for HCC patients.
View Article and Find Full Text PDFExperimental Design: To investigate the antitumor effect of sunitinib and FAK/Pyk2 tyrosine kinase inhibitor (PF-562,271)combination therapy in vivo, utilizing human hepatocellular carcinoma (HCC) cells Huh7.5. Nude rats were inoculated subcutaneously with Huh7.
View Article and Find Full Text PDFBackground: Lytic bone metastases occur frequently in cancer patients and present major clinical issues including lack of effective therapies. The mechanism of lytic bone metastases involves interactions between tumor cells, bone matrix, and bone cells. Both focal adhesion kinase (FAK) and Pyk2 are implicated in the biology and physiology of bone and cancer.
View Article and Find Full Text PDFIn older humans, bone elongation ceases, periosteal expansion continues, and bone remodeling remains a dominant metabolic process. An appropriate animal model of type I and type II osteoporosis would be a species with sealed growth plates and persistence of bone remodeling. The rat is commonly used as a primary model, but due to delayed epiphyseal closure with continuous modeling and lack of Haversian remodeling, Food and Drug Administration guidelines recommend assessment of bone quality in an additional, non rodent, remodeling species.
View Article and Find Full Text PDFA series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
View Article and Find Full Text PDFIn both clinical and experimental settings, access to quantitative methods enabling the objective evaluation of cortical bone mass, structure, geometry and strength are essential for the assessment of efficacy and safety of different treatments aimed to improve bone strength. The ability of non-invasive methodologies (DXA, pQCT and micro-CT) to assess and quantify cortical bone mass and geometry was tested in a nude rat model in which bone loss was induced by surgical castration. Treatment with a bone antiresorptive (alendronate) or a bone forming (PTH) drug was used to: (A) validate the nude rat model in terms of bone metabolism, (B) test the ability of each technology to detect change in cortical bone geometry and (C) correlate cortical bone geometry with bone strength data obtained by 3-point bending method.
View Article and Find Full Text PDFThe three main organs affected by metastasis of all cancers include lungs, liver, and bone. Clinical confirmation of tumor spread to these organs is a negative prognostic sign that marks the stage when disease is rarely curable. Today, treatment of bone metastases is primarily palliative.
View Article and Find Full Text PDFStatins are very potent inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis at the mevalonate level. Today there is an increasing tendency to treat hypercholesterolemia aggressively, hence, the greater use of statins worldwide. The pleiotropic effect of statins is well documented.
View Article and Find Full Text PDFMicro-computed tomography (micro-CT) allows for classical anatomical imaging well suited to the study of skeletal structures. Recent improvements in spatial resolution and the ability to assess cancellous bone microstructure more efficiently has led to an increase in the number of micro-CT users in both academic and commercial environments. Accurate and reproducible positioning of bone samples and image acquisition time are two limiting factors that every bio-imaging laboratory must deal with.
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