osteoprotegerin and Adrenal-Hyperplasia--Congenital

Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs), the bone-reabsorbing cells, and osteoblasts (OBs), and the bone-forming cells. This equilibrium is regulated by numerous cytokines, but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/β-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis, respectively. The pro-osteoblastogenic activity of the Wnt/β-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1). RANKL, sclerostin and DKKs-1 are often up-regulated in bone diseases, and they are the target of new monoclonal antibodies.. The authors performed a systematic literature search in PubMed and EMBASE to June 2018, reviewed and selected articles, based on pre-determined selection criteria.. We re-evaluated the role of RANKL, osteoprotegerin, sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases, such as type 1 diabetes mellitus (T1DM), alkaptonuria (AKU), hemophilia A, osteogenesis imperfecta (OI), 21-hydroxylase deficiency (21OH-D) and Prader-Willi syndrome (PWS). To do so, we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways have been investigated, and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed.. The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases. Furthermore, for some of them, bone damage began in childhood but only manifested with age. The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children, although further studies need to be carried out.

Topics: Adrenal Hyperplasia, Congenital; Alkaptonuria; Biomarkers; Bone Remodeling; Bone Resorption; Child; Diabetes Mellitus, Type 1; Hemophilia A; Humans; Intercellular Signaling Peptides and Proteins; Osteogenesis Imperfecta; Osteoprotegerin; Prader-Willi Syndrome; RANK Ligand; Up-Regulation; Wnt Signaling Pathway

The primary treatment for patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is glucocorticoid replacement therapy, which at supraphysiologic levels can result in diminished bone accrual and lead to osteopenia and osteoporosis. Unlike other diseases treated with chronic glucocorticoid therapy, previous studies of patients with 21OHD have not demonstrated a detrimental effect of glucocorticoid treatment on bone mineral density (BMD). It has been postulated that the elevated androgens typically found in these patients have a protective effect on bone integrity, but the precise mechanism remains unknown. We propose that the inhibitory effect of corticosteroid therapy on bone formation is counteracted by estrogen's effect on bone resorption through the RANK-L/osteoprotegerin (OPG) system. A better understanding of the mechanism by which patients with 21OHD are protected against bone loss may lead to novel therapeutic measures to prevent or treat osteopenia and osteoporosis in other conditions, including postmenopausal women.

Topics: Adrenal Glands; Adrenal Hyperplasia, Congenital; Animals; Bone and Bones; Estrogens; Female; Glucocorticoids; Humans; Male; Models, Biological; Osteoprotegerin; Rats; Steroid 21-Hydroxylase; Steroids; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Case-Control Studies; Cell Differentiation; Cells, Cultured; Child; Child, Preschool; Female; Glucocorticoids; Humans; Male; Osteoclasts; Osteoprotegerin; RANK Ligand; T-Lymphocytes; Time Factors