ABSTRACT
The laboratory diagnosis of hypophosphatasia (HPP) is primarily based on the precise analysis of circulating serum alkaline phosphatase (ALP) activity, determined by biochemical assays. This analysis requires specific conditions of implementation and interpretation and should always be viewed in the light of the clinical and radiological data. Concerns regarding the normal ranges of ALP with respect to age, regarding ALP values that may overlap those of normal subjects in HPP patients, regarding apparently normal ALP values in cases of proven HPP, regarding differential diagnoses that may be responsible for low ALP values outside of HPP will be discussed. High levels of pyridoxal phosphate, a substrate of APL, are of supportive value in the diagnosis of HPP.
Subject(s)
Alkaline Phosphatase/blood , Hypophosphatasia/diagnosis , Biomarkers/blood , Clinical Laboratory Techniques/methods , Diagnosis, Differential , Humans , Hypophosphatasia/blood , Predictive Value of Tests , Pyridoxal Phosphate/blood , Reference Values , Sensitivity and Specificity , Vitamin B Complex/bloodABSTRACT
BACKGROUND: Prader-Willi syndrome (PWS) results from abnormalities in the genomic imprinting process leading to hypothalamic dysfunction with an alteration of growth hormone (GH) secretion. PWS is associated with early morbid obesity and short stature which can be efficiently improved with GH treatment. OBJECTIVES: Our aims were to highlight adipose tissue structural and functional impairments in children with PWS and to study the modifications of those parameters on GH treatment. SUBJECTS AND METHODS: Plasma samples and adipose tissue biopsies were obtained from 23 research centers in France coordinated by the reference center for PWS in Toulouse, France. Lean controls (n=33), non-syndromic obese (n=53), untreated (n=26) and GH-treated PWS (n=43) children were enrolled in the study. Adipose tissue biopsies were obtained during scheduled surgeries from 15 lean control, 7 untreated and 8 GH-treated PWS children. RESULTS: Children with PWS displayed higher insulin sensitivity as shown by reduced glycemia, insulinemia and HOMA-IR compared with non-syndromic obese children. In contrast, plasma inflammatory cytokines such as TNF-α, MCP-1 and IL-8 were increased in PWS. Analysis of biopsies compared with control children revealed decreased progenitor cell content in the stromal vascular fraction of adipose tissue and an impairment of lipolytic response to ß-adrenergic agonist in PWS adipocytes. Interestingly, both of these alterations in PWS seem to be ameliorated on GH treatment. CONCLUSION: Herein, we report adipose tissue dysfunctions in children with PWS which may be partially restored by GH treatment.
Subject(s)
Adipose Tissue/drug effects , Body Height/drug effects , Hormone Replacement Therapy , Human Growth Hormone/therapeutic use , Obesity, Morbid/drug therapy , Pediatric Obesity/drug therapy , Prader-Willi Syndrome/drug therapy , Adipocytes/metabolism , Adipose Tissue/metabolism , Adolescent , Blood Glucose/drug effects , Blood Glucose/metabolism , Body Composition , Child , Child, Preschool , Female , France , Humans , Infant , Lipolysis , Male , Obesity, Morbid/etiology , Obesity, Morbid/metabolism , Pediatric Obesity/etiology , Pediatric Obesity/metabolism , Prader-Willi Syndrome/complications , Prader-Willi Syndrome/metabolism , Treatment Outcome , Young AdultABSTRACT
Growth hormone (GH), secreted by the anterior pituitary into the circulation, binds to membrane receptors in target tissues to stimulate body growth; most of its effects is mediated by the insulin-like growth factor 1 (IGF-1). In addition to promoting growth, GH has important metabolic actions. The syndrome of GH insensitivity (GHI) was first identified in 1966 by Laron et al. in three children with clinical phenotype characteristic of growth hormone deficiency but associated with elevated serum concentration of GH. Direct evidence of a GH receptor (GHR) abnormality was provided in 1989. More recently, molecular abnormalities in the postreceptor signalling mechanism were found. Mutations of signal transducer and activator of transcription 5b (Stat5b) were reported in patients with growth retardation and primary immunodeficiency. Mutations of the tyrosin phosphatase Shp2 were identified in patients affected by Noonan syndrome characterized by short stature, cardiopathy and increased risk of leukaemia. The unmasking of the molecular bases for these defects will contribute greatly to our future understanding of both normal and aberrant growth. Moreover, this knowledge should bring insight on cancerogenesis or immunodeficiency caused by cytokines resistance.
Subject(s)
Human Growth Hormone/genetics , Laron Syndrome/genetics , Receptors, Somatotropin/genetics , Adolescent , Adult , Child , Female , Forecasting , Homozygote , Human Growth Hormone/blood , Humans , Infant, Newborn , Laron Syndrome/blood , Male , Mutation , Noonan Syndrome/genetics , Phenotype , STAT5 Transcription Factor/genetics , Signal Transduction/genetics , Transcription Factors/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
Bone morphogenetic proteins (BMPs) and BMP receptors (BMPRs) are known to regulate the development of calcified tissues by directing mesenchymal precursor cells differentiation. However, their role in the formation of tooth-supporting tissues remains unclear. We investigated the distribution pattern of STRO-1, a marker of mesenchymal progenitor cells and several members of the BMP pathway during the development of mouse molar periodontium, from the post-natal days 6 to 23 (D6 to D23). STRO-1 was mainly localized in the dental follicle (DF) at D6 and 13 then in the periodontal ligament (PDL) at D23. BMP-2 and -7 were detected in Hertwig's epithelial root sheath (HERS) and in DF, then later in differentiated periodontal cells. BMP-3 was detected after D13 of the periodontal development. BMPRs-Ib, -II, the activin receptor-1 (ActR-1) and the phosphorylated Smad1 were detected in DF and HERS at D6 and later more diffusely in the periodontium. BMPR-Ia detection was restricted to alveolar bone. These findings were in agreement with others data obtained with mouse immortalized DF cells. These results suggest that STRO-1 positive DF cells may be target of BMPs secreted by HERS. BMP-3 might be involved in the arrest of this process by inhibiting the signaling provided by cementogenic and osteogenic BMPs.
Subject(s)
Antigens, Surface/metabolism , Bone Morphogenetic Protein Receptors/metabolism , Bone Morphogenetic Proteins/metabolism , Mesenchymal Stem Cells/metabolism , Periodontium/cytology , Periodontium/growth & development , Smad1 Protein/metabolism , Activin Receptors/metabolism , Animals , Bone Morphogenetic Protein 2 , Bone Morphogenetic Protein 3 , Bone Morphogenetic Protein 7 , Bone Morphogenetic Protein Receptors, Type I/metabolism , Bone Morphogenetic Protein Receptors, Type II/metabolism , Cell Differentiation , Cementogenesis , Dental Sac/cytology , Dental Sac/metabolism , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred ICR , Molar/embryology , Molar/metabolism , Phosphorylation , Transforming Growth Factor beta/metabolismABSTRACT
Important data have recently been added to our knowledge of bone mineral metabolism in children. Molecular pathophysiology of several pediatric syndromes has been clarified. Specially, the components of endocrine and metabolic regulations are tightly related with regard to the trophicity of bone. On another hand, the impact of several therapeutics of bone diseases like biphosphonates, parathormone (PTH) or growth hormone on bone anabolism is now strongly emphasized. All these points are important for the becoming of bone pediatric diseases in the adult life. Here we analyze the essential components of mineral metabolism and of its regulation in view of the recent biological data, like PTH/PTHrP (PTH-related peptide)-evoked cell signaling, the role of FGF 23 (Fibroblast growth factor 23) in hypophosphatemia and the regulation of vitamin D metabolism by 1alpha-hydroxylase. Inter-relation of these regulating elements is present in several genetic diseases and in the Mc Cune Albright syndrome. Relationships between metabolic and endocrine factors are analyzed considering their impact on PTH secretion and osteogenesis.
