Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date. METHODS: We performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders. RESULTS: We confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10-13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders. DISCUSSION: Our gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms.

The "dark matter" of DNA and the regulation of bone metabolism: The role of non-coding RNAs.

Epigenetics, present a new discipline that attempts to explain significant differences in phenotypes among patients with the same disease. In contrast to the other epigenetic mechanisms that modulate gene transcription, non-coding RNAs act at the post-transcriptional level. They directly modulate the gene expression of mRNA genes leading to mRNA target cleavage and degradation and translation repression. Bioinformatic predictions indicate that non coding RNAs may be involved in the regulation of 60% of the coding genes and each non-coding RNA can have multiple target genes, and each gene may be regulated by more than one non-coding RNAs. In the last decade several studies have shown a significant role of non-coding RNAs in the regulation of bone metabolism and function of bone cells opening a new era in the understanding of bone biology in health and disease.

Insulin Secretion and Resistance in Normoglycemic Patients with Sickle Cell Disease.

Diabetes mellitus has been described in chronic hemolytic anemias, but data are scarce regarding glucose metabolism in normoglycemic patients. To address this issue, we evaluated insulin sensitivity and secretion in patients with sickle cell disease (SCD) and normal oral glucose tolerance test (OGTT). Forty-five adult patients with homozygous sickle cell disease and Hb S/ß-thalassemia (ß-thal) (mean age 42.5 ± 9.5 years) and 45 healthy individuals matched for age and body mass index (BMI) were included in the study. All participants underwent an oral glucose tolerance test (OGTT) after an overnight fast. All patients had normal OGTT. Fasting glucose values did not differ significantly between groups, however, fasting insulin levels were significantly lower in the patient group compared to the control group (5.1 ± 2.7 µUI/mL vs. 11.3 ± 6.6 µUI/mL, p <0.005, respectively). Pancreatic ß-cell insulin secretion index in the fasting state was significantly lower in patients with sickle cell disease compared with controls as assessed by calculations of the homeostatic model assessment for ß-cell function (HOMA ß%) (77.0 vs. 106.0%, respectively, p <0.001), while HOMA insulin resistance (HOMA IR), was lower in the sickle cell disease patients, albeit not statistically significant (0.8 vs. 1.1, respectively, p = 0.054). The HOMA ß% was significantly correlated with ferritin levels (r = -526, p <0.001) (negative correlation) and with 25-hydroxy (OH)-vitamin D levels (r = 0.479, p <0.001) (positive correlation), even when adjusted for serum ferritin levels. Normoglycemic patients with sickle cell disease demonstrated impaired ß-cell function with reduced insulin secretion even before OGTT was impaired.

A novel strategy combining magnetic particle hyperthermia pulses with enhanced performance binary ferrite carriers for effective in vitro manipulation of primary human osteogenic sarcoma cells.

The present study examines the heating efficiency of a combination of manganese or cobalt ferrites in a binary (Co- or Mn-) ferrite nanoparticle form with magnetite, covered with citric acid to improve biocompatibility. The nanoparticle synthesis is based on the aqueous co-precipitation of proper salts, a facile, low-cost, environmentally friendly and high yield synthetic approach. By detailed structural and magnetic characterisation, the direct influence of structural and magnetic features on magnetic hyperthermia concludes to optimum heating efficiency. At a second stage, best performing magnetic nanoparticles undergo in vitro testing in three cell lines: one cancer cell line and two reference healthy cell lines. Both binary ferrite (MnFe2O4/Fe3O4 and CoFe2O4/Fe3O4) appear to be internalised and well tolerated by the cells while a versatile hyperthermia protocol is attempted in an effort to further improve their in vitro performance. Within this protocol, hyperthermia sequences are split in two runs with an intermediate 48 h time interval cell incubation stage while in each run a variable field mode (single or multiple pulses) is applied. Single-pulse field mode represents a typical hyperthermia application scheme where cells undergo the thermal shock continuously. On the other hand multiple-pulses mode refers to multiple, much shorter in duration AC field changes (field ON/OFFs), at each hyperthermia run, resulting eventually in high heating rate and much more harmful cell treatment. Consequently, we propose a novel series of improved performance heat mediators based on ferrite structures which show maximum efficiency at cancer cells when combined with a versatile multiple-pulse hyperthermia module.

The Contribution of Osteoprogenitor Cells to Arterial Stiffness and Hypertension.

Hypertension, the major cause of cardiovascular disease, is bidirectionally linked to arterial stiffness. Evidence shows that vascular calcification, either medial or intimal, induces arterial stiffening further worsening hypertension parallel to substantially increasing cardiovascular risk. The disturbance in the bone-vascular axis that leads to the increase of calcium deposition in the arterial wall may be the result of a shift in the functionality of bone marrow-derived circulating stem cells with a calcifying potential, namely osteoprogenitor cells. These cells deposit bone matrix proteins in the vascular wall that can subsequently become mineralized. The current notion is that these cells derive from diverse cell lines. The present review summarizes the current knowledge on the role of progenitor cells with a calcifying potential on arterial calcification, stiffness and hypertension.

Anti-osteoporotic drugs and vascular calcification: the bidirectional calcium traffic.

During the last years, numerous epidemiological studies have demonstrated a direct relationship between vascular calcification and low bone mineral density. This observation is in line with experimental data demonstrating the osteogenic characteristics of calcified arteries. Various common risk factors have been suggested to link vascular calcification and bone loss, including aging, estrogen deficiency, vitamin D and K deficiency, diabetes mellitus, renal failure, smoking, chronic inflammation and oxidative stress. Although the underlying pathogenetic mechanisms are not yet clear, current research is focusing on anti-osteoporotic agents that could potentially affect the deposition of calcium in the arterial wall and thus provide an additional therapeutic strategy in elderly osteoporotic women prone to calcific cardiovascular disease.

Familial clustering strongly suggests that the phenotypic variation of the 8344 A>G lys mitochondrial tRNA mutation is encoded in cis.

The maternally inherited 8344 A>G mutation in the mitochondrial Lys tRNA is classically associated with the myoclonic epilepsy, ragged-red muscle fiber (MERRF) syndrome. Multiple lipomatosis (Madelung's disease) is occasionally described. Here we report a large kindred with a statistically significant clustering of very unusual clinical manifestations. We have studied a Greek family that includes seven symptomatic cases of 8344 A>G. Clinical features, glucose tolerance and heteroplasmy in fat, muscle and blood were analyzed. The patients, aged 34-76 at the time of assessment, all suffer from progressive proximal limb-girdle myopathy and extensive lipomatosis. Four of the seven have either impaired glucose tolerance or diabetes but none has had epilepsy, a cardinal feature of MERRF. Heteroplasmy was not higher in adipose tissue than that found in the literature. Compared to literature reports, the familial clustering of this unusual combination of manifestations (lipomatosis in all, epilepsy in none) is statistically significant. The clustering of unusual manifestations in this large kindred strongly suggests that much of the phenotypic variability of 8344 A>G is determined by mitochondrially encoded modifiers in cis.

The renin-angiotensin-aldosterone axis in patients with nontumoral [corrected] hyperprolactinemia.

OBJECTIVE: In physiological conditions, renin-angiotensin-aldosterone (RAA) axis is under continuous tonic inhibition by dopamine. The aim of this study was to evaluate the relationship of nontumoural hyperprolactinemia with the activity of adrenocortical and RAA axis, before and after administration of bromocriptine. DESIGN: Twenty women with nontumoural hyperprolactinemia and 20 healthy women matched for body mass index and age were recruited in this study. All participants were placed on fixed salt intake for 2 weeks before the experiments. The study was conducted in three phases. In phase I, the participants received an intravenous infusion of angiotensin II in three consecutive doses of 2, 4 and 6 ng/kg BW changed every 30 min. In phase II, the patients were started on bromocriptine in gradually increasing doses of 1.25, 2.5, 5, 7.5 and 10 mg/day for 10 weeks. In phase III, the protocol of phase I was repeated in the patient group. Circulating levels of cortisol, plasma renin activity (PRA), aldosterone and prolactin were assayed. RESULTS: Baseline values of prolactin, and PRA (2.6±0.18 nM vs 0.45±0.05 nM P<0.001 and 142.2±14.4 vs 30.7±2.7 pM/h, P<0.001, respectively) but not aldosterone (P=0.081) were significantly higher in the patient group. The angiotensin infusion test induced a significantly greater response in the patient group. Administration of the dopamine agonist restored the basal levels and diminished the response to angiotensin infusion for all the parameters tested. No change in the blood pressure was recorded. CONCLUSIONS: Our study demonstrates that in nontumoural hyperprolactinemia there is an increased reactivity of renin-angiotensin-aldosterone (RAA) axis that is almost completely restored after treatment with a dopamine agonist.

Circulating and Tissue Expression Profile of MicroRNAs in Primary Hyperparathyroidism Caused by Sporadic Parathyroid Adenomas.

We investigated the expression profile of selected microRNAs (miRs) in serum and tissue samples from patients with sporadic parathyroid adenomas (sPAs). This was a prospective, controlled cohort study. Forty patients with sPAs who had undergone parathyroidectomy (PTX) were included. MiR extraction was performed from (i) 40 formalin-fixed paraffin-embedded samples (FFPEs) of sPAs, (ii) 10 FFPEs of normal parathyroid tissue (NPT), (iii) serum samples of the 40 patients with sPAs (t1 = baseline; t2 = 2 months post-PTX), and (vi) serum samples of 10 healthy individuals (controls; t1 = baseline and t2 = 2 months later). Ten miRs were selected based on their interaction with genes related to parathyroid tumorigenesis (miR-17-5p, miR-24-3p, miR-29b-3p, miR-31-5p, miR-135b-5p, miR-186-5p, miR-195-5p, miR-330-3p, miR-483-3p, and miR-877-5p). At tissue level, the relative expression of miR-17-5p, miR-31-5p, miR-135b-5p, miR-186-5p, and miR-330-3p was significantly decreased (fold change [FC]: 0.17, FC: 0.03, FC: 0.01, FC: 0.10, FC: 0.10, respectively; all p values <0.001), and the expression of miR-24-3p and miR-29b-3p was significantly increased (FC: 12.4, p < 0.001; FC: 18.5, p = 0.011, respectively) in sPA compared with NPT samples. The relative expression of miR-135b-5p was also significantly decreased in the serum samples of patients compared with controls (FC: 0.7, p = 0.035). No significant differences were found in the serum samples of patients before and after PTX. MiRs that regulate genes linked to parathyroid tumors such as menin 1 (miR-24-3p, miR-29b-3p), cyclin D1 (miR-17-5p), calcium sensing receptor (miR-31-5p, miR-135b-5p), cyclin-dependent kinase inhibitors (miR-186-5p), and ß-catenin (miR-330-3p) were significantly deregulated in sPAs compared with NPT samples, suggesting a role for epigenetic changes in parathyroid tumorigenesis. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Genetic variation in the visfatin (PBEF1/NAMPT) gene and type 2 diabetes in the Greek population.

Visfatin (NAMPT formerly known as PBEF1) is an adipokine that is strongly expressed in visceral fat and has caused much debate among researchers, regarding its involvement in glucose homeostasis and insulin resistance. It was initially isolated from bone marrow cells, and its involvement in inflammatory procedures such as sepsis and acute lung inflammation is now evident. Several studies have also reported an association of plasma visfatin levels with obesity. We undertook an evaluation of the involvement of the NAMPT gene in the development of type 2 diabetes (T2DM) in the Greek population. We studied 178 patients with T2DM and 177 controls that were matched for sex, age and body mass index. We genotyped three tagging SNPs selected from the HapMap II CEPH European population as reference for the Greek population. These three SNPs tag another 12 SNPs over the entire NAMPT gene with a mean r(2) of 0.92. No indications of association with disease status were found with any of the tested variants or the inferred haplotypes. Results were also negative when the quantitative traits of weight and BMI were tested. Although our study covers common variants across the NAMPT gene, the possible involvement of rare variants in T2DM etiology cannot be ruled out and will require the investigation of very large numbers of cases and controls.

Cinacalcet in hyperparathyroidism secondary to X-linked hypophosphatemic rickets: case report and brief literature review.

X-linked dominant hypophosphatemic rickets (XLH) is the most prevalent genetic form of hypophosphatemic rickets. Standard treatment of XLH patients includes long-term administration of phosphate and calcitriol. Treated patients usually respond well to the conventional therapy and demonstrate amelioration of rachitic symptoms and improved growth. However, long-term administration of phosphate and vitamin D preparations is sometimes complicated with nephrocalcinosis, secondary or tertiary hyperparathyroidism and arterial hypertension. We describe a patient with XLH, caused by a rare missense mutation of the PHEX gene. The patient, while under treatment with alphacalcidol and oral phosphate, developed hypercalciuria, nephrocalcinosis, secondary hyperparathyroidism and arterial hypertension. Cinacalcet was added to the therapeutic regimen and the long-term effects on calciotropic parameters and FGF23 levels are herein reported.

Genetic variation in CARD8, a gene coding for an NLRP3 inflammasome-associated protein, alters the genetic risk for diabetic nephropathy in the context of type 2 diabetes mellitus.

BACKGROUND: Approximately one third of type 2 diabetes mellitus (T2DM) cases present with diabetic nephropathy (DN), the leading cause of end-stage renal disease. Inflammation plays an important role in T2DM disease and DN pathogenesis. NLRP3 inflammasomes are complexes that regulate interleukin-1B (IL-1B) and IL-18 secretion, both involved in inflammatory responses. Activation of NLRP3 is associated with DN onset and progression. Here, we explore whether DN is associated with variants in genes encoding key members of the NLRP3 inflammasome pathway. METHODS: Using genome-wide association data, we performed a pilot case-control association study, between 101 DN-T2DM and 185 non-DN-T2DM cases from the Hellenic population across six NLRP3 inflammasome pathway genes. RESULTS: Three common CARD8 variants confer decreased risk for DN, namely rs11665831 (OR = 0.62, p = 0.016), rs11083925 (OR = 0.65, p = 0.021), and rs2043211 (OR = 0.66, p = 0.026), independent of sex or co-inheritance with an IL-1B variant. CONCLUSION: CARD8 acts as an NLRP3, NF-κB and caspase-1 inhibitor; perhaps, alterations in the cross-talk between CARD8, NF-κB, and NLRP3, which could affect the pro-inflammatory environment in T2DM, render diabetic carriers of certain common CARD8 variants potentially less likely to develop T2DM-related pro-inflammatory responses followed by DN. These preliminary, yet novel, observations will require validation in larger cohorts from several ethnic groups.

The role of cellular senescence in diabetes mellitus and osteoporosis: molecular pathways and potential interventions.

The improving effectiveness of health care leads inevitably to a rapid increase in the elderly population worldwide. At advanced ages, however, people experience chronic disabilities, which significantly increase the social and economic burden while curtailing survival, independence, and quality of life of the aging population. As aging is a multifactorial process, apart from genetic predisposition, other environmental factors, such as chronic sterile inflammation and cellular senescence, contribute as crucial participants and have been targeted to reverse their deleterious effects on tissue homeostasis and functional integrity. Cellular senescence refers to the essentially irreversible inhibition of cellular proliferation when cells are subjected to extrinsic or endogenous stress. Although the process of cellular senescence has long been known, recent evidence demonstrated that it characterizes many aging phenotypes and that elimination of senescent cells at the tissue level can improve age-related tissue dysfunction. These observations have renewed scientific interest in possible therapeutic interventions. Two major chronic diseases associated with aging that impose an enormous burden on global health systems are type 2 diabetes and osteoporosis. This review presents current data on (i) the underlying molecular mechanisms of cellular senescence, (ii) its relationship to these two endocrine diseases that are today prevalent worldwide, and (iii) future prospects of targeted intervention with the aim of simultaneously improving the progression and prognosis of these serious problems of aging.

Hypercalcitoninaemia in pseudohypo-parathyroidism type 1A and type 1B.

Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the parathyroid hormone. Type 1A (PHP1A), which is the most common variant, also include developmental and skeletal defects named as Albright hereditary osteodystrophy (AHO). We present two cases, a 54- and a 33-year-old male diagnosed with PHP who were referred to us for persistently high levels of serum calcitonin. AHO and multinodular goitre were present in the 54-year-old male, while the second patient was free of skeletal deformities and his thyroid gland was of normal size and without nodular appearance. We performed GNAS molecular analysis (methylation status and copy number analysis by MS-MLPA) in genomic DNA samples for both patients. The analysis revealed a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1, in the patient with the clinical diagnosis of PHP1A. This amino acid change appears to be in accordance with the clinical diagnosis of the patient. The genomic DNA analysis of the second patient revealed the presence of the recurrent 3-kb deletion affecting the imprinting control region localised in the STX16 region associated with the loss of methylation (LOM) at the GNAS A/B differentially methylated region and consistent with the diagnosis of an autosomal dominant form of PHP type 1B (PHP1B). In conclusion, hypercalcitoninaemia may be encountered in PHP1A and PHP1B even in the absence of thyroid pathology. Learning points: We describe a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1 as the cause of PHP1A. Hypercalcitoninaemia in PHP1A is considered an associated resistance to calcitonin, as suggested by the generalised impairment of Gsα-mediated hormone signalling. GNAS methylation defects, as in type PHP1B, without thyroid pathology can also present with hypercalcitoninaemia.

Intracerebroventricular infusion of neuropeptide Y increases glucose dependent-insulinotropic peptide secretion in the fasting conscious dog.

The rapid increase of incretins glucose-dependent insulinotropic peptide (GIP) and glucagon like peptide-1 (GLP-1), within 5-15 min, after food ingestion, suggests that a neural mechanism might be involved in the regulation of their secretion. The aim of this study is to determine whether intracerebroventricular (i.c.v) administration of neuropeptide Y (NPY), a widely distributed neurotransmmiter, can mediate this neural regulation of GIP secretion after food consumption. Six healthy mongrel dogs were utilized for this study. A prototype epicranial apparatus was placed surgically, allowing easy and exact localization of the third ventricle for infusions or sampling. Simultaneous blood sampling was obtained from cannulation of a hind limb vein. Plasma insulin, and GIP concentrations were measured after i.c.v infusion of 5, 10 and 25 microg of NPY dissolved in 0.5 ml of artificial cerebrospinal fluid (a CSF). The secretion of GIP and insulin were increased after the injection of NPY in a different pattern. Our data indicate that NPY might be involved in a possible neural control mechanism of GIP secretion after food consumption.

A Role for Circular Non-Coding RNAs in the Pathogenesis of Sporadic Parathyroid Adenomas and the Impact of Gender-Specific Epigenetic Regulation.

Epigenetic changes, including altered small non-coding RNAs, appear to be implicated in the pathogenesis of sporadic parathyroid adenomas (PAs). In this study, we investigated the circular RNAs (circRNAs) expression profile in sporadic PAs. Sixteen tissue samples of sporadic PAs, and four samples of normal parathyroid tissue (NPT) were investigated. Sample preparation and microarray hybridization were performed based on the Arraystar's standard protocols, and circRNAs sequences were predicted by bioinformatics tools. We identified 35 circRNAs that were differentially expressed in sporadic PAs compared to NPT; 22 were upregulated, and 13 were downregulated, according to the pre-defined thresholds of fold-change > 2.0 and p< 0.05. In the subgroup analysis of PAs from male patients (n = 7) compared to PAs from female patients (n = 9), we also find a different expression profile. In particular, 19 circRNAs were significantly upregulated, and four circRNAs were significantly downregulated in male patients, compared to female counterparts. We show here for the first time a differential circRNA expression pattern in sporadic PAs compared to NPT, and a different expression profile in PA samples from male compared to female patients, suggesting an epigenetic role in the PA pathogenesis, and also an effect of gender in the epigenetic regulation of PAs.

Changes of Circulating MicroRNAs in Response to Treatment With Teriparatide or Denosumab in Postmenopausal Osteoporosis.

Context: Expression of microRNAs (miRs) related to bone metabolism in the serum may be affected by antiosteoporotic treatment. Objective: To investigate the effect of two antiosteoporotic agents with opposite effects on bone metabolism on miR expression profile in the serum. Design: Observational, open label, nonrandomized clinical trial. Setting: The outpatient clinics for Metabolic Bone Diseases of 424 General Military Hospital, Thessaloniki, Greece. Patients and Interventions: Postmenopausal women with low bone mass were treated with either teriparatide (TPTD; n = 30) or denosumab (n = 30) for 12 months. Main Outcome Measures: Changes in the serum expression of selected miRs linked to bone metabolism at 3 and 12 months of treatment. Secondary measurements: associations of measured miRs with changes in bone mineral density (BMD) at 12 months and the bone turnover markers (BTMs) C-terminal cross-linking telopeptide of type I collagen and procollagen type I N-terminal propeptide at 3 and 12 months. Results: We found significantly decreased relative expression of miR-33-3p at 3 months (P = 0.03) and of miR-133a at 12 months (P = 0.042) of TPTD treatment. BMD values at 12 months of TPTD treatment were significantly and inversely correlated with miR-124-3p expression at 3 months (P = 0.008). Relative expression of miR-24-3p and miR-27a was correlated with changes in BTMs during TPTD treatment and of miR-21-5p, miR-23a-3p, miR-26a-5p, miR-27a, miR-222-5p, and miR-335-5p with changes in BTMs during denosumab treatment. Conclusions: Circulating miRs are differentially affected by treatment with TPTD and denosumab. TPTD affects the relative expression of miRs related to the expression of RUNX-2 (miR-33) and DKK-1 gene (miR-133).

Assessment of association between lipoxygenase genes variants in elderly Greek population and type 2 diabetes mellitus.

BACKGROUND: Inflammation plays a pivotal role in the pathogenesis of diabetes and its complications. Arachidonic acid lipoxygenases have been intensively studied in their role in inflammation in metabolic pathways. Thus, we aimed to explore variants of lipoxygenase genes (arachidonate lipoxygenase genes) in a diabetes adult population using a case-control study design. METHODS: Study population consisted of 1285 elderly participants, 716 of whom had type 2 diabetes mellitus. The control group consisted of non-diabetes individuals with no history of diabetes history and with a glycated haemoglobin <6.5% (<48 mmol/mol)] and fasting plasma glucose levels <126 mg/dL. Blood samples were genotyped on Illumina Infinium PsychArray. Variants of ALOX5, ALOX5AP, ALOX12, ALOX15 were selected. All statistical analyses were undertaken within PLINK and SPSS packages utilising permutation analysis tests. RESULTS: Our findings showed an association of rs9669952 (odds ratio = 0.738, p = 0.013) and rs1132340 (odds ratio = 0.652, p = 0.008) in ALOX5AP and rs11239524 in ALOX5 gene with disease (odds ratio = 0.808, p = 0.038). Rs9315029 which is located near arachidonate ALOX5AP also associated with type 2 diabetes mellitus ( p = 0.025). No variant of ALOX12 and ALOX15 genes associated with disease. CONCLUSION: These results indicate a potential protective role of ALOX5AP and 5-arachidonate lipoxygenase gene in diabetes pathogenesis, indicating further the importance of the relationship between diabetes and inflammation. Larger population studies are required to replicate our findings.

The role of the Wnt signaling pathway in osteoblast commitment and differentiation.

Wnts are a large family of proteins that participate in an array of cellular biological processes such as embryogenesis, organogenesis and tumor formation. These proteins bind to membrane receptor complexes comprised of a frizzled (Fz) G-protein-coupled receptor and other membrane co-receptors forming molecular groups that initiate, at least, three different intracellular signaling cascades leading to nuclear generation of transcription factors which regulate various cellular events. These events result in selective cellular differentiation, reduction or inhibition of the apoptotic mechanisms or changes in the biologic behavior of various cell lines. During the last decade, canonical Wnt signaling has been shown to play a significant role in the control of osteoblastogenesis and bone formation. In several clinical cases, mutations have been found in the Wnt receptor complexes that are associated with changes in bone mineral density and fractures. Loss-of-function mutations in LRP5 receptors cause, osteoporosis-pseudoglioma syndrome, while gain-of-function mutations in the same group lead to high bone mass phenotypes. Furthermore, osteocytes secrete proteins such as sclerostin, which blocks the membrane complex activation by Wnt, resulting in inhibition of bone formation. Studies of knockout and transgenic mouse models for Wnt pathway components have demonstrated that canonical signaling regulates most aspects of osteoblast physiology including commitment, differentiation, bone matrix formation/mineralization and apoptosis as well as coupling to osteoclastogenesis and bone resorption. Future studies in this rapidly growing area of research can possibly lead to the identification of targets of pharmacological intervention useful in the management of osteoporosis. In the present review we summarized the current knowledge related to the various components of the Wnt signaling pathway, the ways they cooperate in inducing and directing transcriptional functions as well as the interacting points with the TGFbeta superfamily. We also outlined a probable working integrating model of the mechanism of bone formation.

PTH and PTHR1 in osteocytes. New insights into old partners.

Parathyroid hormone receptors are present in bone cells and play a crucial role in the maintenance of skeletal integrity, bone homeostasis and regulation of calcium and phosphate metabolism. Although the function of these receptors has long being recognized in the cells of the osteoblastic lineage regulating directly osteoblast differentiation and function and indirectly osteoclastogenesis, recent findings demonstrate their functional presence in osteocytes participating in the co-ordination of bone remodelling. In this review we focus on the key roles of these receptors in osteoblasts and osteocytes, combining what is known and what is new regarding these interesting pleiotropic hormone receptors.