Abstract
Children with 21-hydroxylase deficiency (21-OHD) need chronic glucocorticoid (cGC) therapy to replace congenital deficit of cortisol synthesis, and this therapy is the most frequent and severe form of drug-induced osteoporosis. In this study, we enrolled 18 patients (9 females) and 18 sex- and age-matched controls. We found in 21-OHD patients high serum and leukocyte levels of dickkopf-1 (DKK1), a secreted antagonist of the Wnt/β-catenin signaling pathway known to be a key regulator of bone mass. In particular, we demonstrated by flow cytometry, confocal microscopy, and real-time PCR that monocytes, T lymphocytes, and neutrophils from patients expressed high levels of DKK1, which may be related to the cGC therapy. In fact, we showed that dexamethasone treatment markedly induced the expression of DKK1 in a dose- and time-dependent manner in leukocytes. The serum from patients containing elevated levels of DKK1 can directly inhibit in vitro osteoblast differentiation and receptor activator of NF-κB ligand (RANKL) expression. We also found a correlation between both DKK1 and RANKL or COOH-terminal telopeptides of type I collagen (CTX) serum levels in 21-OHD patients on cGC treatment. Our data indicated that DKK1, produced by leukocytes, may contribute to the alteration of bone remodeling in 21-OHD patients on cGC treatment.
MeSH terms
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Adolescent
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Adrenal Hyperplasia, Congenital / blood*
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Adrenal Hyperplasia, Congenital / drug therapy*
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Alkaline Phosphatase / metabolism
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Anti-Inflammatory Agents / pharmacology
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Blotting, Western
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Bone Density / drug effects
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Bone Density / genetics
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CD2 Antigens / biosynthesis
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CD2 Antigens / genetics
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Cell Differentiation / drug effects
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Child
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Child, Preschool
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Dexamethasone / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Female
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Flow Cytometry
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Glucocorticoids / adverse effects*
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Glucocorticoids / therapeutic use
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Humans
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Intercellular Signaling Peptides and Proteins / blood*
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Intercellular Signaling Peptides and Proteins / genetics
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Leukocytes / drug effects
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Leukocytes / metabolism*
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Lipopolysaccharide Receptors / biosynthesis
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Lipopolysaccharide Receptors / genetics
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Male
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Microscopy, Confocal
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Neutrophils / drug effects
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Neutrophils / metabolism
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Osteoblasts / drug effects
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Osteoblasts / metabolism
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RANK Ligand / biosynthesis
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Real-Time Polymerase Chain Reaction
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Steroid 21-Hydroxylase / blood*
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Steroid 21-Hydroxylase / genetics
Substances
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Anti-Inflammatory Agents
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CD2 Antigens
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DKK1 protein, human
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Glucocorticoids
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Intercellular Signaling Peptides and Proteins
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Lipopolysaccharide Receptors
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RANK Ligand
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TNFSF11 protein, human
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Dexamethasone
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Steroid 21-Hydroxylase
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Alkaline Phosphatase
Supplementary concepts
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Congenital adrenal hyperplasia due to 21 hydroxylase deficiency