Relationships between osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL), and growth hormone (GH) secretory status in short children.

GH deficiency places children at risk for decreased bone density and increased fracture rates. The RANKL/RANK/OPG system plays an important role in linking bone formation to bone resorption. Although OPG is thought to be secreted as a compensatory response to states of low bone density, its concentrations have not been found to differ significantly between GH-deficient, acromegalic, and healthy adults. AIM: To evaluate the associations between OPG and RANKL serum levels and GH secretory status in children. CHILDREN: 54 short children were recruited. METHODS: Serum OPG and RANKL, IGF-I, IGFBP-3, stimulated GH levels, bone DEXA results, and growth velocity were assessed. Regression modeling was used to evaluate significant predictors of OPG and RANKL levels. RESULTS: There were no significant differences in OPG and RANKL serum levels or bone DEXA results between GH-deficient and GH-sufficient children. A statistically significant quadratic relationship between OPG and IGFBP-3 concentrations was observed. CONCLUSIONS: IGFBP-3 was found to be the only significant predictor of OPG serum levels, allowing us to speculate that increased OPG levels may represent a compensatory response to the missing anabolic actions of IGF-I and/or GH in children with GH deficiency.

Nuclear factor-kappaB p65 facilitates longitudinal bone growth by inducing growth plate chondrocyte proliferation and differentiation and by preventing apoptosis.

NF-kappaB is a group of transcription factors involved in cell proliferation, differentiation, and apoptosis. Mice deficient in the NF-kappaB subunits p50 and p52 have retarded growth, suggesting that NF-kappaB is involved in bone growth. Yet, it is not clear whether the reduced bone growth of these mice depends on the lack of NF-kappaB activity in growth plate chondrocytes. Using cultured rat metatarsal bones and isolated growth plate chondrocytes, we studied the effects of two NF-kappaB inhibitors (pyrrolidine dithiocarbamate (PDTC) or BAY11-7082 (BAY)), p65 short interference RNA (siRNA), and of the overexpression of p65 on chondrocyte proliferation, differentiation, and apoptosis. To further define the underlying mechanisms, we studied the functional interaction between NF-kappaB p65 and BMP-2 in chondrocytes. PDTC and BAY suppressed metatarsal linear growth. Such growth inhibition resulted from decreased chondrocyte proliferation and differentiation and from increased chondrocyte apoptosis. In cultured chondrocytes, the inhibition of NF-kappaB p65 activation (by PDTC and BAY) and expression (by p65 siRNA) led to the same findings observed in cultured metatarsal bones. In contrast, overexpression of p65 in cultured chondrocytes induced chondrocyte proliferation and differentiation and prevented apoptosis. Although PDTC, BAY, and p65 siRNA reduced the expression of BMP-2 in cultured growth plate chondrocytes, the overexpression of p65 increased it. The addition of Noggin, a BMP-2 antagonist, neutralized the stimulatory effects of p65 on chondrocyte proliferation and differentiation, as well as its anti-apoptotic effect. In conclusion, our findings indicate that NF-kappaB p65 expressed in growth plate chondrocytes facilitates growth plate chondrogenesis and longitudinal bone growth by inducing BMP-2 expression and activity.

Association between inadequate sleep and insulin resistance in obese children.

OBJECTIVE: To analyze the relationships between sleep duration, obstructive sleep apnea syndrome (OSAS), and markers of insulin resistance in obese children. STUDY DESIGN: Forty obese children were evaluated for sleep-related complaints. Each child underwent a polysomnogram, an oral glucose tolerance test (OGTT), and fasting lipid panel tests. Indices of insulin resistance (HOMA-IR and WBISI) and insulin secretion (IGI) were calculated based on the results of the OGTT. Markers of insulin resistance were compared among groups categorized according to polysomnogram results. RESULTS: Subjects with shorter sleep duration had higher fasting insulin, peak insulin, and HOMA-IR levels and lower WBISI levels, findings suggestive of insulin resistance. In contrast, differences in body mass index z scores were not observed. Subjects with OSAS (32 of 40 children) had higher triglyceride levels and HOMA-IR values than those without OSAS, but did not differ in sleep duration. Multiple linear regression analysis revealed that HOMA-IR was significantly correlated with age, sleep duration, and percentage of rapid-eye-movement sleep. CONCLUSIONS: Insulin resistance in obese children is associated with short sleep duration and OSAS.