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      Impact of the Uremic Milieu on the Osteogenic Potential of Mesenchymal Stem Cells

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          Abstract

          Human mesenchymal stem cells (hMSCs), the precursors of osteoblasts during osteogenesis, play a role in the balance of bone formation and resorption, but their functioning in uremia has not been well defined. To study the effects of the uremic milieu on osteogenic properties, we applied an in vitro assay culturing hMSCs in osteogenic medium supplemented with serum from healthy donors and from uremic patients on hemodialysis. Compared to control, serum from uremic patients induces, in hMSC cultures, a modification of several key regulators of bone remodeling, in particular a reduction of the ratio Receptor Activator of Nuclear factor Kappa B Receptor (RANKL) over osteoprotegerin, indicating an adaptive response of the system to favor osteogenesis over osteoclastosis. However, the levels of osteopontin, osteocalcin, and collagen type I, are increased in cell medium, while BMP-2, and alizarin red staining were decreased, pointing to a reduction of bone formation favoring resorption. Selected uremic toxins, such as p-cresylsulfate, p-cresylglucuronide, parathyroid hormone, indoxyl sulfate, asymmetric dimethylarginine, homocysteine, were able to mimic some of the effects of whole serum from uremic patients. Serum from cinacalcet-treated patients antagonizes these effects. Hydrogen sulfide (H2S) donors as well as hemodialysis treatment are able to induce beneficial effects. In conclusion, bone modifications in uremia are influenced by the capability of the uremic milieu to alter hMSC osteogenic differentiation. Cinacalcet, H2S donors and a hemodialysis session can ameliorate the hampered calcium deposition.

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          Most cited references 43

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          Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

          Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism. Copyright 2004 Massachusetts Medical Society
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            Osteopontin: a versatile regulator of inflammation and biomineralization.

            Osteopontin is a secreted glycoprotein with a multidomain structure and functions characteristic of a matricellular protein. Osteopontin interacts with cell surface receptors via arginine-glycine-aspartate (RGD)- and non-RGD containing adhesive domains, in addition to binding to components of the structural extracellular matrix. While normally expressed in bone and kidney, osteopontin levels are elevated during wound healing and inflammation in most tissues studied to date. Since 1986, over one thousand studies have been published on osteopontin, including recent experiments in osteopontin-deficient mice. These studies reveal osteopontin as a cell adhesive, signaling, migratory, and survival stimulus for various mesenchymal, epithelial, and inflammatory cells, in addition to being a potent regulator of osseous and ectopic calcification. Based on these reports, a general picture of osteopontin as an important regulator of inflammation and biomineralization is emerging. A common denominator in osteopontin function in these situations is its ability to regulate the function of macrophage and macrophage-derived cells (i.e. osteoclasts). While we have learned much about osteopontin and the processes it appears to regulate over the past decade, many questions regarding this important multifunctional protein remain unanswered and provide important directions for future studies.
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              Homocysteine as a predictive factor for hip fracture in older persons.

              The increased prevalence of osteoporosis among people with homocystinuria suggests that a high serum homocysteine concentration may weaken bone by interfering with collagen cross-linking, thereby increasing the risk of osteoporotic fracture. We examined the association between the total homocysteine concentration and the risk of hip fracture in men and women enrolled in the Framingham Study. We studied 825 men and 1174 women, ranging in age from 59 to 91 years, from whom blood samples had been obtained between 1979 and 1982 to measure plasma total homocysteine. The participants in our study were followed from the time that the sample was obtained through June 1998 for incident hip fracture. Sex-specific, age-adjusted incidence rates of hip fracture were calculated for quartiles of total homocysteine concentrations. Cox proportional-hazards regression was used to calculate hazard ratios for quartiles of homocysteine values. The mean (+/-SD) plasma total homocysteine concentration was 13.4+/-9.1 micromol per liter in men and 12.1+/-5.3 micromol per liter in women. The median duration of follow-up was 12.3 years for men and 15.0 years for women. There were 41 hip fractures among men and 146 among women. The age-adjusted incidence rates per 1000 person-years for hip fracture, from the lowest to the highest quartile for total homocysteine, were 1.96 (95 percent confidence interval, 0.52 to 3.41), 3.24 (0.97 to 5.52), 4.43 (1.80 to 7.07), and 8.14 (4.20 to 12.08) for men and 9.42 (5.72 to 13.12), 7.01 (4.29 to 9.72), 9.58 (6.42 to 12.74), and 16.57 (11.84 to 21.30) for women. Men and women in the highest quartile had a greater risk of hip fracture than those in the lowest quartile--the risk was almost four times as high for men and 1.9 times as high for women. These findings suggest that the homocysteine concentration, which is easily modifiable by means of dietary intervention, is an important risk factor for hip fracture in older persons. Copyright 2004 Massachusetts Medical Society
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2015
                30 January 2015
                : 10
                : 1
                Affiliations
                [1 ]First Division of Nephrology, Department of Cardio-thoracic and Respiratory Sciences, Second University of Naples, School of Medicine, Napoli, Italy
                [2 ]Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, School of Medicine, Napoli, Italy
                [3 ]Nephrology Section Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium
                [4 ]Division of Medical Oncology and Hematology, Department of Clinical and Experimental Medicine, Second University of Naples, School of Medicine, Napoli, Italy
                [5 ]Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
                University of Catania, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: DL AFP DI. Performed the experiments: DL AO AP SG ADN CV VJ JJ. Analyzed the data: DL RV AFP GC JJ DI. Contributed reagents/materials/analysis tools: DL AFP AO RV AP SG ADN CV GC VJ JJ DI. Wrote the paper: DL RV AFP DI.

                Article
                PONE-D-14-45545
                10.1371/journal.pone.0116468
                4312090
                25635832

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 7, Tables: 1, Pages: 17
                Product
                Funding
                This work was supported by the Italian Society of Nephrology (SIN), http://www.sin-italy.org, GRANT “Ricercando 2011” to AFP. Project name: “Exploring the osteogenic properties of mesenchymal stem cells for bone structural –functional repair in hemodialysis patients: role of uremic toxins.” The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                Research Article
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