A SELECTIVE ER-PHAGY EXERTS PROCOLLAGEN QUALITY CONTROL VIA A CALNEXIN-FAM134B COMPLEX

The endoplasmic reticulum (ER) is the largest cellular organelle adapting dynamically to cope with cellular stress and high demand of newly synthesized proteins. Protein misfolding eventually occurs in the ER and leads to protein aggregation and ER dysfunction. Mammals have developed evolutionary-conserved quality control mechanisms at the ER. ER-phagy is a novel identified pathway targeting ER portions via autophagy for lysosomal degradation. This process occurs through ER-phagy receptors, ER proteins that bind autophagosomal LC3 protein via a cytosolic LC3 interacting domain. However, the importance of ER-phagy in maintaining cellular homeostasis is still undiscovered. Moreover, the molecular mechanisms that regulate ER-phagy according to cellular needs are still largely unknown. Chondrocytes and osteoblasts are highly secretory cells with an abundant ER, producing predominantly procollagen (PC) molecules in the extracellular matrix during endochondral ossification. They reside in a poorly vascularized tissue as the growth plate with scarcity of nutrients, representing a good cellular model to study ER-phagy. We have characterized ER- phagy in PC producing cells, serving as a cellular pathway that selectively recognizes misfolded PC in the ER lumen. Specifically we found that the ER chaperone CALNEXIN acts as co-receptor that recognizes ER-luminal misfolded PC and interacts with the ER- phagy receptor FAM134B. In turn, FAM134B binds the autophagosome membrane- associated protein LC3 and delivers a portion of ER containing both CALNEXIN and PC to the lysosome for degradation. Moreover, we identified ER-phagy as a transcriptionally induced mechanism by induction of FAM134B expression during starvation and upon FGF signaling, a critical regulator of chondrocyte differentiation. In vivo, FAM134B knock-down in Medaka fish dampened cartilage growth and bone formation, suggesting a physiological function of ER-phagy during skeletogenesis. Taken together, these data unveil a role for FAM134B-dependent ER-phagy in maintaining cellular fitness in PC producing cells and suggest potential therapeutic approaches for the treatment of skeletal features in multiple human diseases

Gene expression signatures predict response to therapy with growth hormone

Xarxes reguladores de gens; Marcadors predictiusRedes reguladoras de genes; Marcadores predictivosGene regulatory networks; Predictive markersRecombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years. Analysis was performed using 1219 genetic markers and baseline (pre-treatment) blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria for prediction. However, we identified an identical set of genes in both GHD and TS whose expression could be used to classify therapeutic response to r-hGH with a high accuracy (AUC > 0.9). Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management. Trial registration numbers: NCT00256126 and NCT00699855.This work was supported by Merck KGaA, Darmstadt, Germany

Update on statural growth and pubertal development in obese children

Childhood obesity is a growing and alarming problem, associated with several short-term and long-term metabolic and cardiovascular complications. In addition, it has also been suggested that excess adiposity during childhood influences growth and pubertal development. Several studies have shown that during pre-pubertal years, obese patients present higher growth velocity and that this pre-pubertal advantage tends to gradually decrease during puberty, leading to similar final heights between obese and non-obese children. Excess body weight might also influence pubertal onset, leading to earlier timing of puberty in girls. In addition, obese girls are at increased risk of hyperandrogenism and polycystic ovary syndrome. In boys, a clear evidence does not exist: some studies suggesting an earlier puberty associated with the obesity status, whereas other have found a delayed pubertal onset. Overall, the existing evidence of an association between obesity and modification of growth and pubertal patterns underlines a further reason for fighting the epidemics of childhood obesity

Network analysis and juvenile idiopathic arthritis (JIA): a new horizon for the understanding of disease pathogenesis and therapeutic target identification

Juvenile idiopathic arthritis (JIA) is a clinically diverse and genetically complex autoimmune disease. Currently, there is very limited understanding of the potential underlying mechanisms that result in the range of phenotypes which constitute JIA. The elucidation of the functional relevance of genetic associations with phenotypic traits is a fundamental problem that hampers the translation of genetic observations to plausible medical interventions. Genome wide association studies, and subsequent fine-mapping studies in JIA patients, have identified many genetic variants associated with disease. Such approaches rely on ‘tag’ single nucleotide polymorphisms (SNPs). The associated SNPs are rarely functional variants, so the extrapolation of genetic association data to the identification of biologically meaningful findings can be a protracted undertaking. Integrative genomics aims to bridge the gap between genotype and phenotype. Systems biology, principally through network analysis, is emerging as a valuable way to identify biological pathways of relevance to complex genetic diseases. This review aims to highlight recent findings in systems biology related to JIA in an attempt to assist in the understanding of JIA pathogenesis and therapeutic target identification

Defective collagen proteostasis and matrix formation in the pathogenesis of lysosomal storage disorders

The lysosome is a catabolic organelle devoted to the degradation of cellular components, such as protein complexes and whole or portion of organelles that reach the lysosomes through (macro)autophagy. The lysosomes also function as signaling organelles by controlling the activity of key metabolic kinases, such as the mechanistic target of Rapamycin complex 1 (mTORC1). Lysosome dysfunction has dramatic consequences on cellular homeostasis and causes lysosomal storage disorders (LSDs). Here we review the recently proposed mechanisms by which impairment of lysosome/autophagy pathway affects extracellular matrix formation and skeletal development and growth. In particular, we will highlight the role of autophagy as a collagen quality control pathway in collagen-producing cells. An impairment of autophagy, such as the one observed in LSDs, leads to a collagen proteostatic defects and can explain, at least in part, the skeletal phenotypes characterizing patients with lysosomal storage disorders

Growth Hormone Deficiency in Prepubertal Children: Predictive Markers of Cardiovascular Disease

BACKGROUND: Cardiovascular (CV) risk factors have been identified in adults with untreated growth hormone deficiency (GHD). Existing evidence suggests that the development of the atheromatous plaque begins early in childhood. Previous reports have shown that GHD children are prone to increased CV risks including impaired cardiac function, dyslipidemia and abnormalities in body composition. Recent studies in epigenetics and metabolomics have defined specific fingerprints that might be associated with an increased risk of CV disease.AIM: The aim of this review is to point out the most significant biochemical and clinical predictive markers of CV disease in prepubertal children and to evaluate the effect of recombinant human growth hormone therapy on most of these alterations. The novel findings in epigenetics and metabolomics are also reviewed, with a particular focus on translating them into clinical practice.</p