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

Faienza, Maria Felicia; Brunetti, Giacomina; Colucci, Silvia; Piacente, Laura; Ciccarelli, Maria; Giordani, Lucia; Vecchio, Giovanni Carlo Del; D’Amore, Simona; Albanese, L.; Cavallo, Luciano; Grano, Maria

doi:10.1210/jc.2008-2446

Cited by 43 publications

(37 citation statements)

References 33 publications

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“…17 In patients with CAH, RANKL levels are elevated whereas OPG levels are lower than normal. 6 The findings in the present case report are consistent with the literature and suggest that patient had elevated osteoclastic activity. For this reason, the endocrinologist suggested a serum test for vitamin D, which was found to be lower than normal, and the patient was given supplements to increase bone density.…”

Section: Figuresupporting

confidence: 92%

“…7 However, osteoclastogenesis has also been reported in these children as a side effect of long-term glucocorticoid therapy. 6,29 This might have caused the bone destruction in this patient. In addition, osteoclastogenic activity can be monitored by testing the RANKL and OPG levels in the patient's serum.…”

Section: Figurementioning

confidence: 88%

“…5 Increased bone resorption in patients with CAH has been noted in the past and has been related to alterations in receptor activator of nuclear factor-kB ligand (RANKL) and osteoprotegerin (OPG). 6 This effect might be caused by the long-term administration of corticosteroids or the excessive secretion of adrenocorticotropic hormone. 7 Also, bone resorption has been related with loss of teeth in patients with osteolytic diseases.…”

Section: Congenital Adrenal Hyperplasia (Cah)mentioning

confidence: 99%

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Congenital Adrenal Hyperplasia: A Case Report With Premature Teeth Exfoliation and Bone Resorption

2015

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Congenital adrenal hyperplasia (CAH) is an inherited autosomal recessive disorder characterized by insufficient production of cortisol. The aim of this case report was to present a child with CAH, premature exfoliation of primary teeth and accelerated eruption of his permanent teeth related to bone resorption. A 4.5-year-old Caucasian boy with CAH and long-term administration of glucocorticoids was referred for dental restoration. Clinical examination revealed primary molars with worn stainless steel crowns, severe attrition of the upper canines, and absence of the upper incisors. Before the completion of treatment, abnormal mobility of the first upper primary molars and the lower incisors was detected, and a few days later the teeth exfoliated prematurely. Histologic examination revealed normal tooth structure. Alkaline phosphatase and blood cells values were normal. Eruption of the permanent dentition was also accelerated. Tooth mobility was noticed in the permanent teeth as soon as they erupted, along with bone destruction. Examination revealed an elevated level of receptor activator of nuclear factor-kB ligand and lower-than-normal osteoprotegerin and vitamin D levels. The patient was treated with vitamin D

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Section: Figuresupporting

confidence: 92%

Section: Figurementioning

confidence: 88%

Section: Congenital Adrenal Hyperplasia (Cah)mentioning

confidence: 99%

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Congenital Adrenal Hyperplasia: A Case Report With Premature Teeth Exfoliation and Bone Resorption

2015

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“…In our previous work (10), we demonstrated a high osteoclastogenic potential of peripheral blood mononuclear cells in children with 21-OHD on cGC treatment, which seems to be supported by the presence of both circulating osteoclast precursors and T cells, expressing high levels of the proosteoclastogenic cytokine receptor activator of NF-B ligand (RANKL) as well as low amounts of the antiosteoclastogenic molecule osteoprotegerin (OPG). Numerous scientists have highlighted the interactions between bone and immune cells, and in particular, the role of the T cell in osteoclast formation and activity in many diseases, including 21-OHD, has been highlighted (6,10,22). However, little is known about the effect of the immune cell system on the activity of the osteoblasts (OBs), the bone-forming cells, in bone loss-associated diseases and in 21-OHD patients undergoing cGC treatment.…”

mentioning

confidence: 83%

“…In fact, an increased (46), decreased (2,8,12,15,16,20,36,44), or normal BMD (5,13,14,30,47), as well as contrasting results about the evaluation of serum biochemical markers of bone turnover, has been reported in these patients (12,13,36,44). In our previous work (10), we demonstrated a high osteoclastogenic potential of peripheral blood mononuclear cells in children with 21-OHD on cGC treatment, which seems to be supported by the presence of both circulating osteoclast precursors and T cells, expressing high levels of the proosteoclastogenic cytokine receptor activator of NF-B ligand (RANKL) as well as low amounts of the antiosteoclastogenic molecule osteoprotegerin (OPG). Numerous scientists have highlighted the interactions between bone and immune cells, and in particular, the role of the T cell in osteoclast formation and activity in many diseases, including 21-OHD, has been highlighted (6,10,22).…”

mentioning

confidence: 93%

High dickkopf-1 levels in sera and leukocytes from children with 21-hydroxylase deficiency on chronic glucocorticoid treatment

Brunetti

Faienza

Piacente

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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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 agematched controls. We found in 21-OHD patients high serum and leukocyte levels of dickkopf-1 (DKK1), a secreted antagonist of the Wnt/␤-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-B 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.dickkopf-1; 21-hydroxylase deficiency patients; glucocorticoid-induced osteoporosis; leukocytes; glucocorticoids CHILDREN WITH 21-HYDROXYLASE DEFICIENCY (21-OHD), the most common cause of congenital adrenal hyperplasia (CAH) due to deletions or mutations of the P450 21-hydroxylase gene (CYP21), need chronic glucocorticoid (cGC) therapy as soon as the diagnosis has been made to replace congenital deficit in cortisol synthesis and to reduce androgen secretion by adrenal cortex (18). One of the most serious problems of cGC therapy is glucocorticoid-induced osteoporosis (GIO), although the patients are treated with glucocorticoids (GCs) at replacement doses. However, the risk of GC overreplacement or neuroendocrine modifications during treatment (i.e., abnormal growth hormone secretion and pulsatility) should be taken in consideration as potential factors determining bone loss even in subjects treated with apparent "physiological doses" of GCs (29, 54). GIO results in an early, transient increase in bone resorption accompanied by a decrease in bone formation, which is maintained for the duration of GC therapy (3). Therefore, 21-OHD patients are at risk of a great incidence of low bone mass, although studies on bone mineral density (BMD) have reported discordant results. In fact, an increased (46), decreased (2,8,12,15,16,20,36,44), or normal BMD (5, 13, 14, 30, 47), as well as contrasting results about the evaluation of serum biochemical markers of bone turnover, has been reported in these patients (12,13,36,44). In our previous work (10), we demonstrated a high osteoclastogenic potential of peripheral blood mononuclear cells in children with 21-OHD on cGC treatment, which seems to be supported by the pr...

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Peripheral Blood Mononuclear Cells Spontaneous Osteoclastogenesis: Mechanisms Driving the Process and Clinical Relevance in Skeletal Disease

Salamanna

Maglio

Borsari

et al. 2015

Journal Cellular Physiology

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In vitro peripheral blood mononuclear cells differentiate into osteoclasts under the influence of osteoclast-stimulating factors. However, accumulating evidence suggests spontaneous osteoclasts formation and activity in patients affected by local or systemic bone remodeling diseases in comparison with healthy controls. Therefore, within this review, we summarize the studies where spontaneous osteoclastogenesis of peripheral blood mononuclear cells was observed in pathological conditions of the skeletal system. We indicate a linkage between immunoregulation by T cells and spontaneous osteoclasts formation with increased levels of tumor necrosis factors-α, receptor activator of nuclear factor kappa-B ligand and inteleukin-7 production. In the light of these results, it would be of crucial importance to deepen the correlation between systemic bone remodeling diseases and spontaneous osteoclastogenesis as well as to investigate in detail the mechanisms underlying this phenomenon and the clinical relevance in bone remodeling disease diagnosis and monitoring.

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

Abstract: 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.

Cited by 43 publications

References 33 publications

Congenital Adrenal Hyperplasia: A Case Report With Premature Teeth Exfoliation and Bone Resorption

Congenital Adrenal Hyperplasia: A Case Report With Premature Teeth Exfoliation and Bone Resorption

High dickkopf-1 levels in sera and leukocytes from children with 21-hydroxylase deficiency on chronic glucocorticoid treatment

Peripheral Blood Mononuclear Cells Spontaneous Osteoclastogenesis: Mechanisms Driving the Process and Clinical Relevance in Skeletal Disease

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