Adriana Borriello1, Ilaria Caldarelli2, Maria Carmela Speranza2, Saverio Scianguetta3, Annunziata Tramontano2, Debora Bencivenga2, Emanuela Stampone2, Aide Negri4, Bruno Nobili3, Franco Locatelli5, Silverio Perrotta3, Adriana Oliva2, Fulvio Della Ragione6. 1. Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy. Electronic address: adriana.borriello@unina2.it. 2. Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy. 3. Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Second University of Naples, 80138 Naples, Italy. 4. Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi di Firenze, 50134 Firenze, Italy. 5. Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, University of Pavia, Italy. 6. Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy. Electronic address: fulvio.dellaragione@unina2.it.
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. GENERAL SIGNIFICANCE: 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.
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. GENERAL SIGNIFICANCE: 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: Yi Zhou; Jin-Li Meng; Li Feng; Yong-Hong Huang; Jin Ye; Man Li; Zhong-You Xu; Xiang-Wei Li; Fang Yuan; Bin Song Journal: J Int Med Res Date: 2020-03 Impact factor: 1.671