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Osteoclastogenesis in Children with 21-Hydroxylase Deficiency on Long-Term Glucocorticoid Therapy: The Role of Receptor Activator of Nuclear Factor-B Ligand/Osteoprotegerin Imbalance

Departments of Biomedicine of Developmental Age (M.F.F., L.P., M.C., L.G., G.C.D.V., L.C.) and Human Anatomy and Histology (G.B., S.C., M.G.) and Department of Internal Medicine and Public Medicine (M.D., L.A.), Section of Rheumatology, University of Bari, 70100 Bari, Italy

Address all correspondence and requests for reprints to: Maria Felicia Faienza, M.D., Ph.D., Department of Biomedicine of Developmental Age, University of Bari, Bari, Italy, Piazza G. Cesare, 11, 70100 Bari, Italy. E-mail: mf.faienza{at}endobiomol.uniba.it.

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-B 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.