title: Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-α.
abstract: In this study, we investigated the bone cell activity in patients with osteogenesis imperfecta (OI) treated and untreated with neridronate. We demonstrated the key role of Dickkopf-1 (DKK1), receptor activator of nuclear factor-κB ligand (RANKL), and tumor necrosis factor alpha (TNF-α) in regulating bone cell of untreated and treated OI subjects. These cytokines could represent new pharmacological targets for OI.
  
  
  
  Bisphosphonates are widely used in the treatment of children with osteogenesis imperfecta (OI) with the objective of reducing the risk of fractures. Although bisphosphonates increase bone mineral density in OI subjects, the effects on fracture incidence are conflicting. The aim of this study was to investigate the mechanisms underlying bone cell activity in subjects with mild untreated forms of OI and in a group of subjects with severe OI treated with cycles of intravenous neridronate.
  
  
  
  Sclerostin, DKK1, TNF-α, RANKL, osteoprotegerin (OPG), and bone turnover markers were quantified in serum of 18 OI patients (12 females, mean age 8.86 ± 3.90), 8 of which were receiving cyclic intravenous neridronate, and 21 sex- and age-matched controls. The effects on osteoblastogenesis and OPG expression of media conditioned by the serum of OI patients and anti-DKK1 neutralizing antibody were evaluated. Osteoclastogenesis was assessed in cultures from patients and controls.
  
  
  
  DKK1 and RANKL levels were significantly increased both in untreated and in treated OI subjects with respect to controls. The serum from patients with high DKK1 levels inhibited both osteoblast differentiation and OPG expression in vitro. High RANKL and low OPG messenger RNA (mRNA) levels were found in lymphomonocytes from patients. High amounts of TNF-α were expressed by monocytes, and an elevated percentage of circulating CD11b-CD51/CD61+ osteoclast precursors was observed in patients.
  
  
  
  Our study demonstrated the key role of DKK1, RANKL, and TNF-α in regulating bone cell activity of subjects with OI untreated and treated with bisphosphonates. These cytokines could represent new pharmacological targets for OI patients.
authors: Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy. giacomina.brunetti@uniba.it.
authors: G
authors: G
authors: Brunetti
authors: Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children's Hospital, Bari, Italy.
authors: F
authors: F
authors: Papadia
authors: Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children's Hospital, Bari, Italy.
authors: A
authors: A
authors: Tummolo
authors: Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children's Hospital, Bari, Italy.
authors: R
authors: R
authors: Fischetto
authors: Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children's Hospital, Bari, Italy.
authors: F
authors: F
authors: Nicastro
authors: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy.
authors: L
authors: L
authors: Piacente
authors: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy.
authors: A
authors: A
authors: Ventura
authors: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors: G
authors: G
authors: Mori
authors: Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy.
authors: A
authors: A
authors: Oranger
authors: Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy.
authors: I
authors: I
authors: Gigante
authors: Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy.
authors: S
authors: S
authors: Colucci
authors: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy.
authors: M
authors: M
authors: Ciccarelli
authors: Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy.
authors: M
authors: M
authors: Grano
authors: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy.
authors: L
authors: L
authors: Cavallo
authors: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy.
authors: M
authors: M
authors: Delvecchio
authors: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy. mariafelicia.faienza@uniba.it.
authors: M F
authors: MF
authors: Faienza
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins / Q000097:blood; D016723:Bone Remodeling; D002648:Child; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D005819:Genetic Markers; D006023:Glycoproteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D008297:Male; D010010:Osteoclasts / Q000166:cytology; D010012:Osteogenesis; D010013:Osteogenesis Imperfecta / Q000188:drug therapy* / Q000503:physiopathology*; D053244:Osteoprotegerin / Q000097:blood; D053245:RANK Ligand / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; C501126:DKK1 protein, human; D004164:Diphosphonates; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; C422903:SOST protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: DKK1; Osteoblasts; Osteoclasts; Osteogenesis imperfecta; RANKL