Osteoclastogenesis in children with 21-hydroxylase deficiency on long-term glucocorticoid therapy: the role of receptor activator of nuclear factor-kappaB ligand/osteoprotegerin imbalance

J Clin Endocrinol Metab. 2009 Jul;94(7):2269-76. doi: 10.1210/jc.2008-2446. Epub 2009 Apr 28.

Abstract

Context: 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.

MeSH terms

  • Adolescent
  • Adrenal Hyperplasia, Congenital / drug therapy*
  • Adrenal Hyperplasia, Congenital / genetics
  • Adrenal Hyperplasia, Congenital / metabolism
  • Adrenal Hyperplasia, Congenital / physiopathology
  • Case-Control Studies
  • Cell Differentiation / drug effects*
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • Glucocorticoids / therapeutic use*
  • Humans
  • Male
  • Osteoclasts / drug effects
  • Osteoclasts / pathology
  • Osteoclasts / physiology*
  • Osteoprotegerin / genetics
  • Osteoprotegerin / metabolism
  • Osteoprotegerin / physiology*
  • RANK Ligand / genetics
  • RANK Ligand / metabolism
  • RANK Ligand / physiology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Time Factors

Substances

  • Glucocorticoids
  • Osteoprotegerin
  • RANK Ligand
  • TNFRSF11B protein, human
  • TNFSF11 protein, human