TPO
Thyroid peroxidase precursor (EC 1.11.1.8) (TPO)
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Megakaryocytes (MKs) support bone formation by stimulating osteoblasts (OBs) and inhibiting osteoclasts (OCs). Aging results in higher bone resorption, leading to bone loss. Whereas previous studies showed the effects of aging on MK-mediated bone formation, the effects of aging on MK-mediated OC formation is poorly understood. Here we examined the effect of thrombopoietin (TPO) and MK-derived conditioned media (CM) from young (3-4 months) and aged (22-25 months) mice on OC precursors. Our findings showed that aging significantly increased OC formation in vitro. Moreover, the expression of the TPO receptor, Mpl, and circulating TPO levels were elevated in the bone marrow cavity. We previously showed that MKs from young mice secrete factors that inhibit OC differentiation. However, rather than inhibiting OC development, we found that MKs from aged mice promote OC formation. Interestingly, these age-related changes in MK functionality were only observed using female MKs, potentially implicating the sex steroid, estrogen, in signaling. Further, RANKL expression was highly elevated in aged MKs suggesting MK-derived RANKL signaling may promote osteoclastogenesis in aging. Taken together, these data suggest that modulation in TPO-Mpl expression in bone marrow and age-related changes in the MK secretome promote osteoclastogenesis to impact skeletal aging.
Keywords
- aging
- bone marrow macrophage
- megakaryocyte
- osteoclast
- thrombopoietin
NOD.H2 mice are the most commonly used model for human autoimmune thyroiditis. Because thyroid autoimmunity develops slowly (over months), NOD.H2 mice are usually exposed to excess dietary iodide to accelerate and amplify the process. However, unlike the female bias in human thyroid autoimmunity, autoantibodies to thyroglobulin (TgAb) are reported to be similar in male and female NOD.H2 . We sought evidence for sexual dimorphism in other parameters in this strain maintained on regular or iodized water. Without iodide, TgAb levels are higher in males than in females, the reverse of human disease. In humans, autoantibodies to thyroid peroxidase (TPOAb) are a better marker of disease than TgAb. In NOD.H2 mice TPOAb develop more slowly than TgAb, being detectable at 6 months of age versus 4 months for the latter. Remarkably, unlike TgAb, TPOAb levels are higher in female than male NOD.H2 mice on both regular and iodized water. As previously observed, serum T4 levels are similar in both sexes. However, thyroid-stimulating hormone (TSH) levels are significantly higher in males than females with or without iodide exposure. TSH levels correlate with TgAb levels in male NOD.H2 mice, suggesting a possible role for TSH in TgAb development. However, there is no correlation between TSH and TPOAb levels, the latter more important than TgAb in human disease. In conclusion, if the goal of an animal model is to closely reflect human disease, TPOAb rather than TgAb should be measured in older female NOD.H2 mice, an approach requiring patience and the use of mouse TPO protein.
MeSH Terms
- Aging
- Animals
- Antibody Formation
- Autoantibodies
- Diet Therapy
- Disease Models, Animal
- Female
- Humans
- Iodide Peroxidase
- Iodides
- Male
- Mice
- Mice, Inbred NOD
- Sex Characteristics
- Sex Factors
- Thyroglobulin
- Thyroiditis, Autoimmune
- Thyrotropin
Keywords
- NOD.H2h4 mice
- TSH
- sexual dimorphism
- thyroglobulin autoantibodies
- thyroid autoimmunity
- thyroid peroxidase autoantibodies
Previous studies indicate that Kras is dispensable for fetal liver hematopoiesis, but its role in adult hematopoiesis remains unclear. Here, we generated a Kras conditional knockout allele to address this question. Deletion of Kras in adult bone marrow (BM) is mediated by Vav-Cre or inducible Mx1-Cre. We find that loss of Kras leads to greatly reduced thrombopoietin (TPO) signaling in hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), while stem cell factor-evoked ERK1/2 activation is not affected. The compromised TPO signaling is associated with reduced long term- and intermediate-term HSC compartments and a bias toward myeloid differentiation in MPPs. Although granulocyte macrophage colony-stimulating factor (GM-CSF)-evoked ERK1/2 activation is only moderately decreased in Kras(-/-) myeloid progenitors, it is blunted in neutrophils and neutrophil survival is significantly reduced in vitro. At 9-12 months old, Kras conditional knockout mice develop profound hematopoietic defects, including splenomegaly, an expanded neutrophil compartment, and reduced B cell number. In a serial transplantation assay, the reconstitution potential of Kras(-/-) BM cells is greatly compromised, which is attributable to defects in the self-renewal of Kras(-/-) HSCs and defects in differentiated hematopoietic cells. Our results demonstrate that Kras is a major regulator of TPO and GM-CSF signaling in specific populations of hematopoietic cells and its function is required for adult hematopoiesis. Stem Cells 2016;34:1859-1871.
MeSH Terms
- Aging
- Animals
- Cell Compartmentation
- Cell Differentiation
- Cell Self Renewal
- Cell Survival
- Enzyme Activation
- Extracellular Signal-Regulated MAP Kinases
- Gene Deletion
- Granulocyte-Macrophage Colony-Stimulating Factor
- Hematopoiesis
- Hematopoietic Stem Cells
- Integrases
- Mice, Inbred C57BL
- Myeloid Progenitor Cells
- Neutrophils
- Proto-Oncogene Proteins p21(ras)
Keywords
- Adult hematopoiesis
- Cytokine signaling
- Hematopoietic progenitor cells
- Hematopoietic stem cells
- Kras
- Nras
- Stem cell self-renewal
Eltrombopag and romiplostim are thrombopoietin receptor agonists (TPO-RAs) marketed for immune thrombocytopenia (ITP). Thrombotic events have been reported with both drugs. This study was aimed at assessing whether there is a signal for differential risks of thrombosis between these two TPO-RAs. We carried out a disproportionality analysis in the World Health Organization global individual case safety report (ICSR) database (VigiBase(®)). We selected all ICSRs with exposure to a TPO-RA between January 2011 and December 2014. We searched for exposures to eltrombopag or romiplostim in thrombosis reports as compared with other ICSRs, and we calculated adjusted reporting odds ratios (aRORs). We identified 5850 ICSRs, including 764 cases of thrombosis. In multivariate analyses, there was a signal for an increased risk of thrombosis (venous or arterial; aROR 1.72, 95 % confidence interval [CI] 1.47-2.02), venous thrombosis (aROR 1.88, 95 % CI 1.53-2.31), arterial thrombosis (aROR 1.54, 95 % CI 1.18-2.00), ischaemic stroke (aROR 1.65, 95 % CI 1.13-2.42) and myocardial infarction (aROR 1.50, 95 % CI 1.05-2.13) with eltrombopag as compared with romiplostim. Restriction to ICSRs reported by physicians led to similar results. However, worldwide dispensing data for romiplostim and eltrombopag were not accessible, so the rates of thrombosis with both drugs were not normalized by the daily defined doses and the generalizability of the results is limited. This study suggests the presence of a signal for an increased risk of thrombosis with eltrombopag compared with romiplostim. These results must be confirmed and quantified by large aetiological pharmacoepidemiological studies.
MeSH Terms
- Adverse Drug Reaction Reporting Systems
- Aging
- Benzoates
- Humans
- Hydrazines
- Myocardial Infarction
- Pyrazoles
- Receptors, Fc
- Receptors, Thrombopoietin
- Recombinant Fusion Proteins
- Risk Factors
- Stroke
- Thrombopoietin
- Thrombosis
To evaluate the effect of photoinitiators and reducing agents on cure efficiency and color stability of resin-based composites using different LED wavelengths. Model resin-based composites were associated with diphenyl(2,4,6-trimethylbenzoyl) phosphine oxide (TPO), phenylbis(2,4,6-trimethylbenzoyl) phosphine oxide (BAPO) or camphorquinone (CQ) associated with 2-(dimethylamino) ethyl methacrylate (DMAEMA), ethyl 4-(dimethyamino) benzoate (EDMAB) or 4-(N,N-dimethylamino) phenethyl alcohol (DMPOH). A narrow (Smartlite, Dentisply) and a broad spectrum (Bluephase G2, Ivoclar Vivadent) LEDs were used for photo-activation (20 J/cm(2)). Fourier transform infrared spectroscopy (FT-IR) was used to evaluate the cure efficiency for each composite, and CIELab parameters to evaluated color stability (ΔE00) after aging. The UV-vis absorption spectrophotometric analysis of each photoinitiator and reducing agent was determined. Data were analyzed using two-way ANOVA and Tukey's test for multiple comparisons (α=0.05). Higher cure efficiency was found for type-I photoinitiators photo-activated with a broad spectrum light, and for CQ-systems with a narrow band spectrum light, except when combined with an aliphatic amine (DMAEMA). Also, when combined with aromatic amines (EDMAB and DMPOH), similar cure efficiency with both wavelength LEDs was found. TPO had no cure efficiency when light-cured exclusively with a blue narrowband spectrum. CQ-systems presented higher color stability than type-I photoinitiators, especially when combined with DMPOH. After aging, CQ-based composites became more yellow and BAPO and TPO lighter and less yellow. However, CQ-systems presented higher color stability than type-I photoinitiators, as BAPO- and TPO-, despite their higher cure efficiency when photo-activated with corresponding wavelength range. Color matching is initially important, but color change over time will be one of the major reasons for replacing esthetic restorations; despite the less yellowing of these alternative photoinitiators, camphorquinone presented higher color stability.
MeSH Terms
- Acrylic Resins
- Bisphenol A-Glycidyl Methacrylate
- Camphor
- Color
- Composite Resins
- Curing Lights, Dental
- Light
- Light-Curing of Dental Adhesives
- Materials Testing
- Methacrylates
- Phosphines
- Photoinitiators, Dental
- Polyurethanes
- Reducing Agents
- Spectroscopy, Fourier Transform Infrared
Keywords
- Artificial accelerated aging
- Color change
- Degree of conversion
- Light-curing
- Light-curing unit
The CALIPER program has previously reported a comprehensive database of pediatric reference intervals for 63 biochemical and immunochemical markers. Here, covariate-stratified reference intervals were determined for a number of special assays not previously reported. A total of 1917 healthy children and adolescents were recruited and serum concentrations of 14 biochemical markers were measured using the Abbott Architect ci4100 system. Age and gender partitions were statistically determined, outliers removed and reference intervals calculated using CSLI C28-A3 guidelines. Many analytes showed dynamic changes in concentration requiring at least 3 age partitions. Unique intervals were required within the first year of life for: pancreatic amylase, C-peptide, ceruloplasmin, insulin, β-2-microglobulin, cystatin C, dehydroepiandrosterone sulfate (DHEA-S), and α-1-glycoprotein. Cholinesterase, cholinesterase-dibucaine number, and immunoglobulin E required only 2 age partitions and α-1-antitrypsin required only one. Anti-CCP and anti-TPO levels were below the detection limit of the assay. Some analytes including insulin and DHEA-S required additional gender partitions for specific age groups. Complex profiles were observed for endocrine and special chemistry markers, requiring establishment of age- and gender-specific reference intervals. These updated reference intervals will allow improved laboratory assessment of pediatric patients but should be validated for each analytical platform and local population as recommended by CLSI.
MeSH Terms
- Adolescent
- Aging
- Biomarkers
- Blood Chemical Analysis
- Child
- Child, Preschool
- Databases, Factual
- Female
- Growth and Development
- Health
- Humans
- Infant
- Infant, Newborn
- Male
- Reference Values
- Residence Characteristics
Keywords
- Analyte
- Biomarker
- CALIPER
- Pediatric
- Reference intervals