Insulin-like growth factor-I (IGF-I) is an important regulator of endochondral ossification. However, little is known about the signaling pathways activated by IGF-I in growth plate chondrocytes. We have previously shown that NF-B-p65 facilitates growth plate chondrogenesis. In this study, we first cultured rat metatarsal bones with IGF-I and/or pyrrolidine dithiocarbamate (PDTC), a known NF-B inhibitor. The IGF-I-mediated stimulation of metatarsal growth and growth plate chondrogenesis was neutralized by PDTC. In rat growth plate chondrocytes, IGF-I induced NF-B-p65 nuclear translocation. The inhibition of NF-B-p65 expression and activity (by p65 short interfering RNA and PDTC, respectively) in chondrocytes reversed the IGF-I-mediated induction of cell proliferation and differentiation and the IGF-I-mediated prevention of cell apoptosis. Moreover, the inhibition of the phosphatidylinositol 3-kinase and Akt abolished the effects of IGF-I on NF-B activation. In conclusion, our findings indicate that IGF-I stimulates growth plate chondrogenesis by activating NF-B-p65 in chondrocytes. IGF-I2 is a key regulator of longitudinal bone growth, with such role being exerted both during intrauterine and extrauterine life. Knock-out mice for IGF-I exhibit intrauterine growth retardation and experience a subnormal postnatal growth rate (1). A similar growth pattern has been described in a child born with a homozygous IGF-I deletion (2).The fact that IGF-I null mice have a reduced growth plate height clearly suggests a facilitatory role for IGF-I on growth plate chondrogenesis and, in turn, on longitudinal bone growth. The presence of the IGF-I receptor in growth plate chondrocytes also suggests that IGF-I facilitates longitudinal bone growth directly at the growth plate (3, 4). However, little is known about the specific molecular mechanisms responsible for the IGF-I-mediated induction of growth plate chondrogenesis.Mammalian NF-B is a group of transcription factors, including seven members, p65 (RelA), c-Rel, RelB, p50/p105 (NF-B1), and p52/p100 (NF-B2) (5). Upon activation by a wide variety of stimuli (proinflammatory cytokines, growth factors, and viral proteins), NF-B translocates to the nucleus, where it modulates the expression of target genes involved in cell growth, survival, adhesion, and death (6, 7). These target genes include anti-apoptotic (8) as well as pro-apoptotic ones (9), suggesting that the effects of NF-B on cell growth and survival may depend on the cell type and on the nature of the extracellular stimuli.Previous evidence indicates that NF-B exerts a regulatory role in bone growth and development. Mice deficient in both the NF-B subunits p50 and p52 have retarded growth and shortened long bones (10), suggesting that NF-B may be involved in bone formation and growth. In addition, we have recently shown that the NF-B subunit p65 has a facilitatory role on growth plate chondrogenesis (11). Because experimental evidence in a number of cell types suggests a functional interaction between IGF-I and NF-B (12-...

Adolescents with type 1 diabetes typically receive clinical care every 3 months. Between visits, diabetes-related issues may not be frequently reflected, learned, and documented by the patients, limiting their self-awareness and knowledge about their condition. We designed a text-messaging system to help resolve this problem. In a pilot, randomized controlled trial with 30 adolescents, we examined the effect of text messages about symptom awareness and diabetes knowledge on glucose control and quality of life. The intervention group that received more text messages between visits had significant improvements in quality of life.

The role of growth hormone (GH) and its therapeutic supplementation in the trichorhinophalangeal syndrome type I (TRPS I) is not well delineated. TRPS I is a rare congenital syndrome, characterized by craniofacial and skeletal malformations including short stature, sparse, thin scalp hair and lateral eyebrows, pear-shaped nose, cone shaped epiphyses and hip dysplasia. It is inherited in an autosomal dominant manner and caused by haploinsufficiency of the TRPS1 gene. We report a family (Mother and 3 of her 4 children) with a novel mutation in the TRPS1 gene. The diagnosis was suspected only after meeting all family members and comparing affected and unaffected siblings since the features of this syndrome might be subtle. The eldest sibling, who had neither GH deficiency nor insensitivity, improved his growth velocity and height SDS after 2 years of treatment with exogenous GH. No change in growth velocity was observed in the untreated siblings during this same period. This report emphasizes the importance of examining all family members when suspecting a genetic syndrome. It also demonstrates the therapeutic effect of GH treatment in TRPS I despite normal GH-IGF1 axis. A review of the literature is included to address whether TRPS I is associated with: a) GH deficiency, b) GH resistance, or c) GH-responsive short stature. More studies are needed before recommending GH treatment for TRPS I but a trial should be considered on an individual basis.

Kisspeptins (Kiss) have been shown to be key component in the regulation of gonadotropin-releasing hormone (GnRH) secretion. In vitro studies have demonstrated an increase in GnRH gene expression by Kiss suggesting regulation of GnRH at both the secretory and pretranslational levels. Here, we define genetic mechanisms that mediate Kiss action on target gene expression. In vitro, sequential deletions of the mGnRH gene promoter fused to the luciferase (LUC) reporter gene localized a kisspeptin-response element (KsRE) between −3446 bp and −2806 bp of the mGnRH gene. In vivo, transgenic mice bearing sequential deletions of the mGnRH gene promoter linked to the LUC reporter localized an identical KsRE. To define the mechanism of regulation, Kiss was first shown to induce nucleosome-depleted DNA within the KsRE, and a potential binding site for the transcription factor, Otx-2 was revealed. Furthermore, increased Otx-2 mRNA, protein and binding to the KsRE after Kiss treatment was demonstrated. In conclusion, this work identified elements in GnRH-neuronal cell lines and in transgenic mice that mediate positive regulation of GnRH by Kiss. In addition, we show for the first time that Otx-2 is regulated by Kiss, and plays a role in mediating the transcriptional response of mGnRH gene.