title: Impact of the uremic milieu on the osteogenic potential of mesenchymal stem cells.
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.
authors: First Division of Nephrology, Department of Cardio-thoracic and Respiratory Sciences, Second University of Naples, School of Medicine, Napoli, Italy.
authors: Diana
authors: D
authors: Lanza
authors: First Division of Nephrology, Department of Cardio-thoracic and Respiratory Sciences, Second University of Naples, School of Medicine, Napoli, Italy.
authors: Alessandra F
authors: AF
authors: Perna
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, School of Medicine, Napoli, Italy.
authors: Adriana
authors: A
authors: Oliva
authors: Nephrology Section Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium.
authors: Raymond
authors: R
authors: Vanholder
authors: Nephrology Section Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium.
authors: Anneleen
authors: A
authors: Pletinck
authors: Division of Medical Oncology and Hematology, Department of Clinical and Experimental Medicine, Second University of Naples, School of Medicine, Napoli, Italy.
authors: Salvatore
authors: S
authors: Guastafierro
authors: First Division of Nephrology, Department of Cardio-thoracic and Respiratory Sciences, Second University of Naples, School of Medicine, Napoli, Italy.
authors: Annarita
authors: A
authors: Di Nunzio
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, School of Medicine, Napoli, Italy.
authors: Carmela
authors: C
authors: Vigorito
authors: First Division of Nephrology, Department of Cardio-thoracic and Respiratory Sciences, Second University of Naples, School of Medicine, Napoli, Italy.
authors: Giovambattista
authors: G
authors: Capasso
authors: Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany.
authors: Vera
authors: V
authors: Jankowski
authors: Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany.
authors: Joachim
authors: J
authors: Jankowski
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, School of Medicine, Napoli, Italy.
authors: Diego
authors: D
authors: Ingrosso
mesh_terms: D000328:Adult; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000187:drug effects; D000069449:Cinacalcet / Q000494:pharmacology; D024042:Collagen Type I / Q000378:metabolism; D003470:Culture Media; D005260:Female; D006440:Hemofiltration; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D053495:Osteopontin / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D012995:Solubility; D014511:Uremia / Q000097:blood / Q000473:pathology*
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D024042:Collagen Type I; D003470:Culture Media; D053244:Osteoprotegerin; D053245:RANK Ligand; D015675:Osteocalcin; D053495:Osteopontin; D000069449:Cinacalcet
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