title: Iron overload enhances human mesenchymal stromal cell growth and hampers matrix calcification.
abstract: BACKGROUND
  Iron overload syndromes include a wide range of diseases frequently associated with increased morbidity and mortality. Several organs are affected in patients with iron overload including liver, heart, joints, endocrine glands, and pancreas. Moreover, severe bone and hemopoietic tissue alterations are observed. Because of the role of bone marrow mesenchymal stromal cells (BM-MSCs) in bone turnover and hematopoiesis, iron effects on primary BM-MSCs cultures were evaluated.
  
  
  METHODS
  Primary human BM-MSCs cultures were prepared and the effects of iron on their proliferation and differentiation were characterized by biochemical analyses and functional approaches.
  
  
  RESULTS
  Addition of iron to the culture medium strongly increased BM-MSCs proliferation and induced their accelerated S phase entry. Iron enters BM-MSCs through both transferrin-dependent and transferrin-independent mechanisms, inducing the accumulation of cyclins E and A, the decrease of p27(Kip1), and the activation of MAPK pathway. Conversely, neither apoptotic signs nor up-regulation of reactive oxygen species were observed. Iron inhibited both differentiation of BM-MSCs into osteoblasts and in vitro matrix calcification. These effects result from the merging of inhibitory activities on BM-MSCs osteoblastic commitment and on the ordered matrix calcification process.
  
  
  CONCLUSIONS
  We demonstrated that BM-MSCs are a target of iron overload. Iron accelerates BM-MSCs proliferation and affects BM-MSCs osteoblastic commitment, hampering matrix calcification.
  
  
  CONCLUSIONS
  Our study reports, for the first time, that iron, at concentration found in overloaded patient sera, stimulates the growth of BM-MSCs, the BM multipotent stromal cell component. Moreover, iron modulates the physiological differentiation of these cells, affecting bone turnover and remodeling.
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy. Electronic address: adriana.borriello@unina2.it.
authors: Adriana
authors: A
authors: Borriello
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors: Ilaria
authors: I
authors: Caldarelli
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors: Maria Carmela
authors: MC
authors: Speranza
authors: Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Second University of Naples, 80138 Naples, Italy.
authors: Saverio
authors: S
authors: Scianguetta
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors: Annunziata
authors: A
authors: Tramontano
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors: Debora
authors: D
authors: Bencivenga
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors: Emanuela
authors: E
authors: Stampone
authors: Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi di Firenze, 50134 Firenze, Italy.
authors: Aide
authors: A
authors: Negri
authors: Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Second University of Naples, 80138 Naples, Italy.
authors: Bruno
authors: B
authors: Nobili
authors: Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, University of Pavia, Italy.
authors: Franco
authors: F
authors: Locatelli
authors: Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Second University of Naples, 80138 Naples, Italy.
authors: Silverio
authors: S
authors: Perrotta
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors: Adriana
authors: A
authors: Oliva
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy. Electronic address: fulvio.dellaragione@unina2.it.
authors: Fulvio
authors: F
authors: Della Ragione
mesh_terms: D002113:Calcification, Physiologic; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D019190:Iron Overload / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D010006:Osteoblasts / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species
keywords: Iron; Iron overload; Mesenchymal stromal cells; Mineralization; Osteogenesis