scholarly journals Role of Parathyroid Hormone-Related Protein in the Decreased Osteoblast Function in Diabetes-Related Osteopenia

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2027-2035 ◽  
Author(s):  
Daniel Lozano ◽  
Luis F. de Castro ◽  
Sonia Dapía ◽  
Irene Andrade-Zapata ◽  
Félix Manzarbeitia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Glucose ◽  
Ex Vivo ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Related Protein ◽  
Matrix Mineralization ◽  
Parathyroid Hormone Related Protein ◽  
Marrow Ablation

A deficit in bone formation is a major factor in diabetes-related osteopenia. We examined here whether diabetes-associated changes in osteoblast phenotype might in part result from a decrease in PTH-related protein (PTHrP). We used a bone marrow ablation model in diabetic mice by multiple streptozotocin injections. PTHrP (1–36) (100 μg/kg, every other day) or vehicle was administered to mice for 13 d starting 1 wk before marrow ablation. Diabetic mice showed bone loss in both the intact femur and the regenerating tibia on d 6 after ablation; in the latter, this was related to decreased bone-forming cells, osteoid surface, and blood vessels, and increased marrow adiposity. Moreover, a decrease in matrix mineralization occurred in ex vivo bone marrow cultures from the unablated tibia from diabetic mice. These skeletal alterations were associated with decreased gene expression (by real-time PCR) of Runx2, osterix, osteocalcin, PTHrP, the PTH type 1 receptor, vascular endothelial growth factor and its receptors, and osteoprotegerin to receptor activator of nuclear factor-κB ligand mRNA ratio, and increased peroxisome proliferator-activated receptor-γ2 mRNA levels. Similar changes were induced by hyperosmotic (high glucose or mannitol) medium in osteoblastic MC3T3-E1 cells, which were mimicked by adding a neutralizing anti-PTHrP antibody or PTH type 1 receptor antagonists to these cells in normal glucose medium. PTHrP (1–36) administration reversed these changes in both intact and regenerating bones from diabetic mice in vivo, and in MC3T3-E1 cells exposed to high glucose. These findings strongly suggest that PTHrP has an important role in the altered osteoblastic function related to diabetes.

The C-terminal fragment of parathyroid hormone-related protein counteracts the deficient osteogenesis in the bone marrow of diabetic mice

Bone ◽  
2009 ◽  
Vol 44 ◽  
pp. S355
Author(s):  
D. Lozano⁎ ◽  
S. Portal-Nuñez ◽  
L.F. de Castro ◽  
I. Andrade-Zapata ◽  
S. Dapía ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Parathyroid Hormone ◽  
Diabetic Mice ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Terminal Fragment

scholarly journals Activation of Bone Marrow-Derived Cells Angiotensin (Ang) II Type 1 Receptor by Ang II Promotes Atherosclerotic Plaque Vulnerability

2018 ◽  
Vol 19 (9) ◽  
pp. 2621
Author(s):  
Maxime Pellegrin ◽  
Karima Bouzourène ◽  
Jean-François Aubert ◽  
Aimable Nahimana ◽  
Michel Duchosal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mrna Expression ◽  
Atherosclerotic Plaque ◽  
Cholesterol Metabolism ◽  
Mrna Levels ◽  
Ang Ii ◽  
Plaque Vulnerability ◽  
Plaque Development ◽  
Pro Inflammatory Cytokines

Angiotensin (Ang) II triggers vulnerable atherosclerotic plaque development. Bone marrow (BM)-derived cells are key players in atherogenesis but whether Ang II induces plaque vulnerability directly through Ang II type 1 receptor (AT1R) activation on these cells remains to be clarified. In the present study, we investigated whether a lack of AT1R on BM-derived cells might affect Ang II-mediated vulnerable plaque development. The 2-kidney, 1-clip (2K1C) model (Ang II-dependent mouse model of advanced atherosclerosis and vulnerable plaques) was generated in ApoE−/− mice transplanted with AT1aR−/− or AT1aR+/+ BM. Plasma cholesterol as well as hepatic mRNA expression levels of genes involved in cholesterol metabolism were significantly lower in 2K1C mice transplanted with AT1aR−/− BM than in controls. Atherosclerotic lesions were significantly smaller in AT1aR−/− BM 2K1C mice (−79% in the aortic sinus and −71% in whole aorta compared to controls). Plaques from AT1aR−/− BM 2K1C mice exhibited reduced lipid core/fibrous cap and macrophage/smooth muscle cells ratios (−82% and −88%, respectively), and increased collagen content (+70%), indicating a more stable phenotype. Moreover, aortic mRNA levels of pro-inflammatory cytokines IL-12p35, IL-1β, and TNF-α were significantly reduced in AT1aR−/− BM 2K1C mice. No significant differences in either the number of circulating Ly6Chigh inflammatory monocytes and Ly6Clow resident anti-inflammatory monocyte subsets, or in mRNA levels of aortic M1 or M2 macrophage markers were observed between the two groups. No significant differences were observed in splenic mRNA levels of T cell subsets (Th1, Th2, Th17 and Treg) markers between the two groups. In conclusion, direct AT1R activation by Ang II on BM-derived cells promotes hepatic mRNA expression of cholesterol-metabolism-related genes and vascular mRNA expression of pro-inflammatory cytokines that may lead to plaque instability.

scholarly journals The Association of Parathyroid Hormone Related Protein and Vitamin D Level with Serum Calcium Ion in Acute Leukemia Patients

2020 ◽  
Vol 26 (3) ◽  
Author(s):  
Niniek Wiendayanthi ◽  
MI. Diah Pramudianti ◽  
Yuwono Hadisuparto
Keyword(s):  
Bone Marrow ◽  
Vitamin D ◽  
Parathyroid Hormone ◽  
Acute Leukemia ◽  
Serum Calcium ◽  
Calcium Ion ◽  
Receiver Operating Curve ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
D 20

Acute leukemia is bone marrow clonal cell malignancy. One of its complications is hypercalcemia. Parathyroid Hormone-Related Protein (PTHrP) activities involve the regulation of Calcium (Ca) metabolism. Vitamin D is a steroid involved in Ca homeostasis and bone mineralization. This study aimed to analyze PTHrP and vitamin D levels with serum calcium ion in acute leukemia. A cross-sectional study was performed in Clinical Pathology Dr. Moewardi General Hospital Surakarta between July and August 2019, consisting of 41 subjects with new acute leukemia who were diagnosed based on bone marrow puncture and or immunophenotyping result. The cut-off value of Ca ion serum and PTHrP level were determined with a Receiver Operating Curve (ROC). The data were analyzed with a 2x2 table, followed by multivariate logistic regression analysis, and p<0.05 was considered significant. Statistical analysis showed the median age of 25 (2-68) years, 23 (56.10%) ALL, and 18 (43.90%) non-ALL patients. The median of Ca ion and PTHrP were 1.08 (0.84-1.21) mmol/l and 307.52 (20.77-1104.26) pg/mL, respectively. The mean level of vitamin D was 26.45±11.40 ng/mL. Bivariate analysis showed that PTHrP levels ≥ 110.09 pg/mL and vitamin D ≥ 20 ng/mL were related to serum Ca ion ≥ 1.07 mmol/l (PR 4.675; 95% CI: 1.211-18.041; p=0.021 and PR 5.143; 95% CI: 1.279-20.677; p=0.017). Multivariate analysis showed that PTHrP ≥ 110.09 pg/mL and vitamin D ≥ 20 ng/mL were associated with serum Ca ion ≥1.07 mmol/l. There was a significant association between PTHrP, vitamin D level, and serum Ca ion in acute leukemia patients.

Reversal of New-Onset Type 1 Diabetes in Mice and Induction of FoxP3+ Regulatory T Cells by Syngeneic Bone Marrow Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4857-4857
Author(s):  
Jian Ouyang ◽  
Yanting Wen ◽  
Junhao Chen ◽  
Yong Liu ◽  
De Pei Wu
Keyword(s):  
Bone Marrow ◽  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Bone Marrow Transplantation ◽  
Glucose Tolerance ◽  
Marrow Transplantation ◽  
Diabetic Mice ◽  
Insulin Levels ◽  
New Onset

Abstract Objective: Autologous bone marrow transplantation (ABMT) was introduced as a novel strategy to treat new-onset type 1 diabetes (T1D). Induction of CD4+CD25+ FoxP3+T regulatory lymphocytes (Tregs) helps maintain self-tolerance in autoimmune diabetes. Here, we were tying to investigate the effects of syngeneic bone marrow transplantation (syn-BMT) in T1D mice models and to investigate the role of Tregs in this context. Research design and methods: Syn-BMT was used to mimic the ABMT to T1D patients in human. Fraternal inbred multiple low doses of streptozotocin (mld-SZ) induced diabetic mice were used as both donors (n = 7) and recipients (n = 20). And normal fraternal inbred mice were also used as donors (n=13). After total body irritation to recipient mice, syn-BMT was given either on day 10 or on day 40 of T1D. Blood and urine glucose was observed. On day120 after syn-BMT, glucose tolerance was tested and then mice were killed. Insulin levels in sera were tested by ELISA and pancreata histological and morphometry were analyzed by HE staining. Tregs in spleens were tested by Flow cytometry analysis, FoxP3 protein was tested by western blot, and FoxP3 mRNA was tested by real time PCR. Results: Syn-BMT, if applied when T1D is new-onset (10 d), can reverse blood glucose to close to normoglycemia without farther relapse, maintain blood insulin levels, improve glucose tolerance and ameliorate pancreata destruction. Syn-BMT leading to recovery of T1D results in the induction of Tregs, increased Foxp3 protein and mRNA expression in both the groups of diabetic mice receiving syn-BMT with either diabetic or normal donors. However, if given on a later disease stage (40 d), although syn-BMT helped reduce blood glucose for about 66 d and improved pancreata histological and morphometry, it showed relapse of diabetes further and decrement of insulin levels. Interestingly, this group did not show the increment of Tregs, Foxp3 protein or mRNA expression. Conclusions: This study provided a rationale to treat human new-onset T1D with autologous HSC. Syn-BMT, if given when T1D is new-onset, is safe and is able to reverse the diabetic status. The induction of Tregs and Foxp3 in both mRNA and protein levels as the results of syn-BMT, may contribute to the immune tolerance after syn-BMT, and the observed improvement of new-onset T1D.

Axl/ Mer Inhibitor ONO-9330547 As a Novel Therapeutic Agent in a Stromal Co-Culture Model of Primary Acute Myeloid Leukaemia (AML)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2754-2754 ◽  
Author(s):  
Marie Gilmour ◽  
Anna Scholtz ◽  
Oliver G. Ottmann ◽  
Robert K Hills ◽  
Steven Knapper ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Research Funding ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Flow Cytometric Analysis ◽  
Transcript Level ◽  
High Rate ◽  
Bone Marrow Niche ◽  
Mrna Levels

Abstract The TAM kinase family are a group of receptor kinases involved in the regulation of many cellular processes including proliferation, cell survival and cytokine production. Consequently this group is frequently overexpressed or aberrantly activated in a variety of cancers including AML, where overexpression of Axl or its ligand Gas6 confers a poor prognosis particularly amongst FLT3-ITD mutated AMLs. ONO-9330547 is a highly potent Axl/Mer inhibitor which shows improved target selectivity compared to other orally available Axl inhibitors in leukaemic cells and spares normal CD34+ bone marrow cells predicting minimal toxicity. We examined a cohort of 70 primary AMLs Ex vivo for ONO-9330547 drug sensitivity and determined low micromolar EC50s in 60% of patient samples (Average EC50=3.16µM+/-3.49). Phospho-Axl was rapidly reduced in response to ONO-9330547 and downstream pro-survival targets AKT, S6 and ERK1/2 were concurrently suppressed. Dose dependant induction of apoptosis was observed in conjunction with suppression of the Axl ligand, Gas6. Synergistic interaction of ONO-9330547 with the chemotherapeutic drug Cytarabine was observed (Mean combination index =0.59), suggesting combination therapy to be a useful strategy with the development of Axl inhibitors. There was no association of ONO-9330547 sensitivity with any clinical characteristics within the patient cohort, however the samples from the commonly-occurring NPM1 mutant/ cytogenetically normal AML subgroup were significantly more sensitive to ONO-9330547 than WT or FLT3-ITD samples (p=0.004 lower EC50). mRNA levels of TAM family members Axl, Mer, Tyro3 and Gas6 were generally low in diagnostic patient material, although those with high levels of ≥1 of the TAM kinases were associated with drug resistance. This was confirmed through flow cytometric analysis of phospho-Axl, where similarly high basal activation of Axl correlated with increased EC50 values. Given the high rate of relapse and drug resistance in AML and the potential for microenvironment mediated protection of AML blasts in the bone marrow niche, we investigated the effects of ONO-9330547 in stromal co-culture models. Stimulation of basal p-Axl and Gas6 was observed through the addition of cytokines and adhesion of AML blasts to the stromal layer. In contrast to low levels of Gas6 at the transcript level, Gas6 was readily detectable in patient plasma samples and blasts co-cultured on primary AML-derived stromal layers compared to normal bone marrow stroma. Co-culture completely abrogated the efficacy of ONO-9330547 on AML blasts, significantly blocked apoptotic response and Axl/Gas 6 knockdown. In summary, constitutive or stroma- inducible levels of Gas6 ligand direct ONO-9330547 sensitivity in diagnostic AML patient samples. These data provide a pre-clinical assessment of ONO-9330547 in AML and provide rationale for further investigation of this compound in combination with both traditional and novel therapies that may disrupt microenvironment-mediated up-regulation of the Axl/Gas6 signalling pathway. Disclosures Gilmour: ONO pharmaceuticals: Research Funding. Ottmann:Fusion Pharma: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Hills:TEVA: Honoraria. Knapper:ONO pharmaceuticals: Research Funding; Novartis: Honoraria, Other: Travel and expenses for international conferences. Zabkiewicz:ONO pharmaceuticals: Research Funding.

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