title: Osteoclastogenesis in children with 21-hydroxylase deficiency on long-term glucocorticoid therapy: the role of receptor activator of nuclear factor-kappaB ligand/osteoprotegerin imbalance.
abstract: BACKGROUND
  Children with 21-hydroxylase deficiency (21-OHD) need chronic glucocorticoid (cGC) therapy to replace congenital deficit of cortisol synthesis. cGC therapy is the most frequent and severe form of drug-induced osteoporosis, and different mechanisms have been proposed to explain its pathogenesis.
  
  
  OBJECTIVE
  We investigated the osteoclastogenic potential of peripheral blood mononuclear cells (PBMCs) from 18 children with 21-OHD on cGC therapy and 25 controls who never received GCs. We also evaluated the presence of circulating osteoclast precursors (OCPs) and the role of T cells in osteoclast formation.
  
  
  RESULTS
  Spontaneous osteoclastogenesis, without adding macrophage-colony stimulating factor and receptor activator of nuclear factor-kappaB ligand (RANKL), and significantly higher osteoclasts resorption activity occurred in 21-OHD patients. Conversely, macrophage-colony stimulating factor and RANKL were essential to trigger and sustain osteoclastogenesis in controls. Furthermore, in 21-OHD patients, we identified a significant percentage of CD11b-CD51/CD61 and CD51/61-RANK-positive cells, which are OCPs strongly committed. Additionally, we demonstrated a T cell-dependent osteoclastogenesis from 21-OHD patients' PBMCs. T cells from patients expressed high levels of RANKL and low levels of osteoprotegerin (OPG) with respect to controls. Moreover, 21-OHD patients had higher soluble RANKL and lower OPG serum levels compared with controls; thus, soluble RANKL to OPG ratio was significantly higher in patients than controls.
  
  
  CONCLUSIONS
  The present study showed for the first time a high osteoclastogenic potential of PBMCs from 21-OHD patients on cGC therapy. This spontaneous osteoclastogenesis seems to be supported by both the presence of circulating OCPs and factors released by T cells.
authors.affiliation: Department of Biomedicine of Developmental Age, University of Bari, Bari, Italy, Piazza G. Cesare, 11, 70100 Bari, Italy. mf.faienza@endobiomol.uniba.it
authors.forename: Maria Felicia
authors.initials: MF
authors.lastname: Faienza
authors.forename: Giacomina
authors.initials: G
authors.lastname: Brunetti
authors.forename: Silvia
authors.initials: S
authors.lastname: Colucci
authors.forename: Laura
authors.initials: L
authors.lastname: Piacente
authors.forename: Maria
authors.initials: M
authors.lastname: Ciccarelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Giordani
authors.forename: Giovanni Carlo
authors.initials: GC
authors.lastname: Del Vecchio
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amore
authors.forename: Livia
authors.initials: L
authors.lastname: Albanese
authors.forename: Luciano
authors.initials: L
authors.lastname: Cavallo
authors.forename: Maria
authors.initials: M
authors.lastname: Grano
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D005938:Glucocorticoids; D053244:Osteoprotegerin; D053245:RANK Ligand; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human