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Szulc P.,University of Lyon | Schoppet M.,University of Marburg | Rachner T.D.,Dresden University Medical Center | Chapurlat R.,University of Lyon | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism

Context: Experimental data show that dickkopf-1 (DKK1) may be involved in the regulation of arterial calcification. However, clinical data on the association between serum DKK1 levels and severity of abdominal aortic calcification (AAC) are scarce. Objective: Our aim was to determine the association between serum DKK1 concentration and AAC severity in men. Design: This is a cross-sectional analysis in the STRAMBO cohort. Setting: The cohort was recruited from the general population. Participants: We examined 1139 male volunteers aged 20 to 87 years. No specific exclusion criteria were used. Interventions: We collected blood samples and assessed AAC severity on the lateral spine scans obtained by a Discovery A Hologic device using the semiquantitative Kauppila score. Main Outcome Measures: We tested the hypothesis that low DKK1 levels are associated with AAC severity in men. Results: In men aged 20 to 60 years, serum DKK1 levels were not associated with other variables. In men aged 60 years and older, lower DKK1 levels were associated with higher odds of severe AAC (AAC score >5). After adjustment for confounders, odds of severe AAC increased with decreasing DKK1 levels (odds ratio = 1.42, 95% confidence interval = 1.13-1.79, P < .005) and was higher below vs above the median DKK1 level (odds ratio = 2.19, 95% confidence interval = 1.37-3.49, P < .005). Heavy smoking, hypertension, ischemic heart disease, and elevated levels of fibroblast growth factor 23 were associated with severe AAC significantly, independently of DKK1 and additively with low DKK1 levels. Conclusion: In older men, lower serum DKK1 levels are associated with severe AAC regardless of age and other potential confounders. Copyright © 2014 by the Endocrine Society. Source

Tsourdi E.,TU Dresden | Rijntjes E.,Charite - Medical University of Berlin | Kohrle J.,Charite - Medical University of Berlin | Hofbauer L.C.,TU Dresden | And 2 more authors.

Thyroid hormones are key regulators of bone homeostasis, and Wnt signaling has been implicated in thyroid hormone-associated bone loss. Here we tested whether hyperthyroidism and hypothyroidism interfere with dickkopf-1 (DKK1) and sclerostin, two inhibitors of Wnt signaling. Twelveweek-old male C57BL/6 mice were rendered either hyperthyroid or hypothyroid. Hyperthyroid mice displayed decreased trabecular (-54%, P<.001) and cortical bone density (-5%, P<.05) and reduced cortical thickness (-15%, P<.001), whereas hypothyroid mice showed a higher trabecular bone density (-26%, P<.001) with unchanged cortical bone parameters. Histomorphometry and biochemical markers of bone remodeling indicated high bone turnover in hyperthyroid mice and low bone turnover in hypothyroid mice. In vivo, serum DKK1 concentrations were decreased in hyperthyroid mice (-24%, P < .001) and increased in hypothyroid mice (-18%, P < .01). The increase of thenumberof DKK1-positive cells in hypothyroid mice was confirmed at the tissue level. Interestingly, sclerostin was increased in both disease models, although to a higher extent in hyperthyroid mice (-50%, P<.001, and -24%, P<.05). Serum sclerostin concentrations adjusted for bone mass were increased by 3.3-fold in hyperthyroid (P < .001) but not in hypothyroid mice. Consistently, sclerostinmRNAexpression and thenumberof sclerostin-positive cells were increased in hyperthyroid but not in hypothyroid mice. Our data show that thyroid hormone-induced changes in bone remodeling are associated with a divergent regulation of DKK1 and sclerostin. Thus, the modulation of Wnt signaling by thyroid hormones may contribute to thyroid hormoneassociated bone disease and altered expression of Wnt inhibitors may emerge as potential therapeutic targets. © 2015 by the Endocrine Society. Source

Arabanian L.S.,TU Dresden | Kujawski S.,TU Dresden | Kujawski S.,Center for Regenerative Therapies | Habermann I.,TU Dresden | And 3 more authors.
British Journal of Haematology

Signal transduction pathways in megakaryocytes, a rare population of bone marrow cells, are poorly understood. We have previously shown that the calcineurin-dependent transcription factor Nuclear Factor of Activated T cells (NFAT) is expressed in megakaryocytes and is required for the transcription of specific megakaryocytic genes. The biological role of NFAT in megakaryocytes, however, is unknown. Here we show that activation of the calcineurin/NFAT pathway in megakaryocytes forces the cells to go into apoptosis. Calcineurin/NFAT activation in megakaryocytes leads to membrane expression of Fas ligand (FASLG), a pro-apoptotic member of the tumour necrosis factor superfamily. Expression of FASLG was augmented in cells stably overexpressing NFATC2 and suppressed in cells either pretreated with the calcineurin inhibitor ciclosporin A (CsA) or expressing the specific peptide inhibitor of NFAT, VIVIT. In cocultures with Fas-expressing Jurkat T cells, the presence of activated megakaryocytic cells, but not of unstimulated cells or cells stimulated in the presence of CsA, significantly induced apoptosis in Jurkat cells in a Fas/FASLG- and NFAT-dependent manner. These results represent the first evidence for a biological function of the calcineurin/NFAT pathway in megakaryocytes, and suggest that the biological role of megakaryocytes may include the induction of apoptosis in bystander cells. © 2011 Blackwell Publishing Ltd. Source

Szulc P.,University of Lyon | Hawa G.,BioMedica | Boutroy S.,University of Lyon | Vilayphiou N.,University of Lyon | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism

Context: Osteoprotegerin (OPG) is an inhibitor of bone resorption, but its relationship to bone microarchitecture remains unclear. Objective: Our objective was to study the relationship between OPG concentration and bone microarchitecture in men. Design, Setting, and Participants: We conducted a cross-sectional study of a population-based cohort of 1149 men aged 20-87 yr. Interventions: We assessed bone microarchitecture at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (XtremeCT Scanco) and measured serum OPG concentration and bone turnover markers: osteocalcin, bone-specific alkaline phosphatase, N-terminal extension type I collagen propeptide, C-terminal type 1 collagen telopeptide, and urinary deoxypyridinoline. Main outcome measures: Differences were assessed in bone microarchitectural parameters across the OPG quartiles in the models adjusted for age, weight, height, physical activity, ischemic heart disease, diabetes mellitus, calcium intake, serum levels of free testosterone, bioavailable 17β-estradiol, PTH, 25-hydroxycholecalciferol, and creatinine. Results: After adjustment for the confounders, men in the highest (fourth) quartile of OPG levels (>4.55pmol/liter)hadhighertotal cross- sectionalareaandtrabecularareaatthedistalradiusanddistal tibia (3.3-6.0%, P < 0.05). At both skeletal sites, the highest OPG quartile was associated with lower cortical thickness (8.2%, P < 0.001, and 3.7%, P < 0.05) and volumetric bone mineral density (vBMD, 2.7%, P < 0.001, and 1.6%, P < 0.005) compared with the three lower quartiles combined. Associations of OPG level with trabecular vBMD, number, thickness, and distribution were not significant. Men in the fourth OPG quartile had higher levels of bone resorption markers (11.8-13.1%, P < 0.01-0.001). Conclusions: Men with higher serum OPG concentration had lower cortical thickness and vBMD, probably due to accelerated endo- and intracortical bone turnover, but higher cross-sectional area possibly due to periosteal apposition. Copyright © 2011 by The Endocrine Society. Source

Stopp S.,Medical Clinic and Policlinic I | Bornhauser M.,Medical Clinic and Policlinic I | Bornhauser M.,Center for Regenerative Therapies | Ugarte F.,University Hospital Carl Gustav Carus | And 5 more authors.

The melanoma cell adhesion molecule defines mesenchymal stromal cells in the human bone marrow that regenerate bone and establish a hematopoietic microenvironment in vivo. The role of the melanoma cell adhesion molecule in primary human mesenchymal stromal cells and the maintenance of hematopoietic stem and progenitor cells during ex vivo culture has not yet been demonstrated. We applied RNA interference or ectopic overexpression of the melanoma cell adhesion molecule in human mesenchymal stromal cells to evaluate the effect of the melanoma cell adhesion molecule on their proliferation and differentiation as well as its influence on co-cultivated hematopoietic stem and progenitor cells. Knockdown and overexpression of the melanoma cell adhesion molecule affected several characteristics of human mesenchymal stromal cells related to osteogenic differentiation, proliferation, and migration. Furthermore, knockdown of the melanoma cell adhesion molecule in human mesenchymal stromal cells stimulated the proliferation of hematopoietic stem and progenitor cells, and strongly reduced the formation of long-term culture-initiating cells. In contrast, melanoma cell adhesion molecule-overexpressing human mesenchymal stromal cells provided a supportive microenvironment for hematopoietic stem and progenitor cells. Expression of the melanoma cell adhesion molecule increased the adhesion of hematopoietic stem and progenitor cells to human mesenchymal stromal cells and their migration beneath the monolayer of human mesenchymal stromal cells. Our results demonstrate that the expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells determines their fate and regulates the maintenance of hematopoietic stem and progenitor cells through direct cell-cell contact. ©2013 Ferrata Storti Foundation. Source

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