High levels of LIGHT/TNFSF14 in patients with Prader-Willi syndrome.

PURPOSE/METHODS: Prader-Willi syndrome (PWS) is a rare genetic disorder displaying different clinical features, including obesity and bone impairment. LIGHT/TNFSF14 is a cytokine produced by immune cells affecting both fat and bone metabolism. The present study aimed to evaluate LIGHT serum levels in 28 children and 52 adult PWS patients compared to age and sex-matched controls, as well as correlations with parameters of bone and fat metabolism. RESULTS: Median serum LIGHT levels were significantly increased in pediatric PWS with respect to controls [255.82 (284.43) pg/ml vs 168.11 (76.23) pg/ml, p ≤ 0.02] as well as in adult PWS compared to controls [296.85 (895.95) pg/ml vs 134.18 (141.18) pg/ml, p ≤ 0.001]. In pediatric PWS, LIGHT levels were positively correlated with weight-SDS, height-SDS, and glucose levels, and negatively with total 25 (OH) vitamin D, cholesterol, LDL cholesterol and triglycerides. Additionally, LIGHT levels were negatively correlated with total BMD and fat mass. In adult PWS, LIGHT levels were positively correlated with weight, HDL cholesterol and PTH, and negatively with glucose, insulin, HOMA-IR, total cholesterol, LDL cholesterol, triglycerides, calcium, phosphorus, 25(OH)Vitamin D as well as with instrumental parameters of bone and fat quality. Consistently, multiple regression analysis showed that LIGHT serum levels in pediatric and adult PWS were predicted by different parameters including 25 (OH) Vitamin D as well as DXA parameters of bone and fat quality. CONCLUSIONS: In PWS children and adults the high levels of LIGHT could represent a marker of the altered bone and fat metabolism.

Role of Wnt-signaling inhibitors DKK-1 and sclerostin in bone fragility associated with Turner syndrome.

PURPOSE: Girls affected with Turner syndrome (TS) present with low bone mineral density (BMD) and osteopenia/osteoporosis. Thus, they have an increased risk to develop fractures compared to normal population. The aim of this study was to deepen the pathophysiology of skeletal fragility in TS subjects by evaluating the serum levels of Dickkopf-1 (DKK-1) and sclerostin, main regulators of bone mass, as well as the percentage of circulating osteoblast precursors (OCPs). METHODS: Thirty-four TS girls and 24 controls were recruited. All subjects underwent anthropometric measures (height, weight, body mass index-BMI). A peripheral venous blood sample was collected to determine serum levels of active intact parathyroid hormone (PTH), 25-OH vitamin D, calcium, phosphorus, bone alkaline phosphatase (bALP), osteocalcin, sclerostin, DKK-1, RANKL and OPG. OCPs were detected by flow cytometry. In TS subjects bone mineralization was measured at lumbar spine by dual energy X-ray absorptiometry (DXA). RESULTS: bALP, 25-OH Vitamin D, and osteocalcin levels were significant lower in TS subjects than in the controls. Statistically significant higher levels of sclerostin, DKK-1 and RANKL were measured in patients compared with the controls. The percentage of OCPs did not show significant differences between patients and controls. Sclerostin and DKK-1 levels were related with anthropometric parameters, bone metabolism markers, HRT, rhGH therapy, RANKL and lumbar BMAD-Z-score. CONCLUSION: TS patients showed higher levels of sclerostin and DKK-1 than controls which can be related to HRT, and to reduced bone formation markers as well as the increased bone resorption activity.

Analysis of Circulating Mediators of Bone Remodeling in Prader-Willi Syndrome.

We tested the hypothesis that the levels of bone remodeling mediators may be altered in Prader-Willi syndrome (PWS). We assessed RANKL, OPG, sclerostin, DKK-1 serum levels, and bone metabolism markers in 12 PWS children (7.8 ± 4.3 years), 14 PWS adults (29.5 ± 7.2 years), and 31 healthy controls matched for sex and age. Instrumental parameters of bone mineral density (BMD) were also evaluated. Lumbar spine BMD Z-scores were reduced in PWS children (P < 0.01), reaching osteopenic levels in PWS adults. PWS patients showed lower 25(OH)-vitamin D serum levels than controls (P < 0.001). Osteocalcin was increased in PWS children but reduced in adults respect to controls (P < 0.005 and P < 0.01, respectively). RANKL levels were higher in both pediatric and PWS adults than controls (P < 0.004), while OPG levels were significantly reduced (P < 0.004 and P < 0.006, respectively). Sclerostin levels were increased in children (P < 0.04) but reduced in adults compared to controls (P < 0.01). DKK-1 levels did not show significant difference between patients and controls. In PWS patients, RANKL, OPG, and sclerostin significantly correlated with metabolic and bone instrumental parameters. Consistently, with adjustment for age, multiple linear regression analysis showed that BMD and osteocalcin were the most important predictors for RANKL, OPG, and sclerostin in children, and GH and sex steroid replacement treatment in PWS adults. We demonstrated the involvement of RANKL, OPG, and sclerostin in the altered bone turnover of PWS subjects suggesting these molecules as markers of bone disease and new potential pharmacological targets to improve bone health in PWS.

Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-α.

UNLABELLED: In this study, we investigated the bone cell activity in patients with osteogenesis imperfecta (OI) treated and untreated with neridronate. We demonstrated the key role of Dickkopf-1 (DKK1), receptor activator of nuclear factor-κB ligand (RANKL), and tumor necrosis factor alpha (TNF-α) in regulating bone cell of untreated and treated OI subjects. These cytokines could represent new pharmacological targets for OI. INTRODUCTION: Bisphosphonates are widely used in the treatment of children with osteogenesis imperfecta (OI) with the objective of reducing the risk of fractures. Although bisphosphonates increase bone mineral density in OI subjects, the effects on fracture incidence are conflicting. The aim of this study was to investigate the mechanisms underlying bone cell activity in subjects with mild untreated forms of OI and in a group of subjects with severe OI treated with cycles of intravenous neridronate. METHODS: Sclerostin, DKK1, TNF-α, RANKL, osteoprotegerin (OPG), and bone turnover markers were quantified in serum of 18 OI patients (12 females, mean age 8.86 ± 3.90), 8 of which were receiving cyclic intravenous neridronate, and 21 sex- and age-matched controls. The effects on osteoblastogenesis and OPG expression of media conditioned by the serum of OI patients and anti-DKK1 neutralizing antibody were evaluated. Osteoclastogenesis was assessed in cultures from patients and controls. RESULTS: DKK1 and RANKL levels were significantly increased both in untreated and in treated OI subjects with respect to controls. The serum from patients with high DKK1 levels inhibited both osteoblast differentiation and OPG expression in vitro. High RANKL and low OPG messenger RNA (mRNA) levels were found in lymphomonocytes from patients. High amounts of TNF-α were expressed by monocytes, and an elevated percentage of circulating CD11b-CD51/CD61+ osteoclast precursors was observed in patients. CONCLUSIONS: Our study demonstrated the key role of DKK1, RANKL, and TNF-α in regulating bone cell activity of subjects with OI untreated and treated with bisphosphonates. These cytokines could represent new pharmacological targets for OI patients.

Growth hormone release during insulin tolerance, clonidine, arginine and growth hormone releasing hormone tests in short normal children and adolescents.

This study was retrospectively performed in 574 short normal children and adolescents [328 underwent insulin tolerance test (ITT), 34 clonidine test (CLON), 64 arginine test (ARG), 19 GHRH test, 52 ITT+CLON, 30 GHRH+CLON, and 47 ITT+CLON+GHRH) in order to evaluate the effect of pubertal stage on GH response to different tests and to identify the most likely mechanism of action of different stimuli. GH peak was higher during GHRH than in all other tests. Sex or start of pubertal development did not cause any GH peak difference. Low-responder (GH peak less than 10 ng/ml) percentages were similar (ITT = 13.5%, CLON = 13.4%, ARG = 13.2%, GHRH = 10.6%) also when the subjects were divided according to sex and pubertal development. ITT+CLON showed discordant results in 42/99 subjects (30/42 = 71.4% were low-responders to ITT and 12/42 = 28.6% to CLON). GH peak appeared earlier during GHRH (85% less than 45 min) and later during CLON (78%: 60-120 min) than during all other tests; GH peak during ITT showed a wide variability of time. Negative correlations were found between GH peak during GHRH and chronological age, height and bone age and during CLON and chronological age. In conclusion our data show that these tests have similar GH secretagogue reliability.