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Journal RefereesJournal of Bone and Mineral Research, PLoS ONE, Biophysica Acta, Thrombosis and Haemostasis, Circulation Research, Hormone and Metabolic Research, International Journal of Inflammation, Experimental and Clinical Endocrinology and Diabetes, Journal Biochimica et Biophysica Acta (BBA - General Subjects), European Journal of Endocrinology
Publications (36) View all
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Dataset: Supplemental data
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Article: Macrophage-Derived Matrix Vesicles: An Alternative Novel Mechanism for Microcalcification in Atherosclerotic Plaques.
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ABSTRACT: Rationale: We previously showed that early calcification of atherosclerotic plaques associates with macrophage accumulation. Chronic renal disease (CRD) and mineral imbalance accelerates calcification and the subsequent release of matrix vesicles (MVs) - precursors of microcalcification. Objective: We tested the hypothesis that macrophage-derived MVs contribute directly to microcalcification. Methods and Results: Macrophages associated with regions of calcified vesicular structures in human carotid plaques (n=136 patients). In vitro, macrophages released MVs with high calcification and aggregation potential. MVs expressed exosomal markers (CD9 and TSG101), and contained S100A9 and annexin V (Anx5). Silencing S100A9 in vitro and genetic deficiency in S100A9(-/-) mice reduced MV calcification, while stimulation with S100A9 increased calcification potential. Externalization of phosphatidylserine (PS) after Ca/P stimulation and interaction of S100A9 and Anx5, indicated that a PS-Anx5-S100A9 membrane complex facilitates hydroxyapatite nucleation within the macrophage-derived MV membrane. Conclusions: Our results support the novel concept that macrophages release calcifying MVs enriched in S100A9 and Anx5, which contribute to accelerated microcalcification in CRD.Circulation Research 04/2013; · 9.49 Impact Factor -
Article: MicroRNA in Cardiovascular Calcification: Focus on Targets and Extracellular Vesicle Delivery Mechanisms.
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ABSTRACT: Cardiovascular calcification is a prominent feature of chronic inflammatory disorders-such as chronic kidney disease, type 2 diabetes mellitus, and atherosclerosis-that associate with significant morbidity and mortality. The concept that similar pathways control both bone remodeling and vascular calcification is widely accepted, but the precise mechanisms of calcification remain largely unknown. The central role of microRNAs (miRNA) as fine-tune regulators in the cardiovascular system and bone biology has gained acceptance and has raised the possibility for novel therapeutic targets. Additionally, circulating miRNAs have been proposed as biomarkers for a wide range of cardiovascular diseases, but knowledge of miRNA biology in cardiovascular calcification is very limited. This review focuses on the role of miRNAs in cardiovascular disease, with emphasis on osteogenic processes. Herein, we discuss the current understanding of miRNAs in cardiovascular calcification. Furthermore, we identify a set of miRNAs common to diseases associated with cardiovascular calcification (chronic kidney disease, type 2 diabetes mellitus, and atherosclerosis), and we hypothesize that these miRNAs may provide a molecular signature for calcification. Finally, we discuss this novel hypothesis with emphasis on known biological and pathological osteogenic processes (eg, osteogenic differentiation, release of calcifying matrix vesicles). The aim of this review is to provide an organized discussion of the known links between miRNA and calcification that provide emerging concepts for future studies on miRNA biology in cardiovascular calcification, which will be critical for developing new therapeutic strategies.Circulation Research 03/2013; 112(7):1073-84. · 9.49 Impact Factor -
Article: Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus.
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ABSTRACT: OBJECTIVE: Type 2 diabetes mellitus results in increased risk of fracture and delayed fracture healing. ZDF fa/fa rats are an established model of type 2 diabetes mellitus with low bone mass and delayed bone healing. We tested whether a sclerostin-neutralizing antibody (Scl-AbVI) would reverse the skeletal deficits of diabetic ZDF rats. METHODS: Femoral defects of 3 mm were created in 11-week old diabetic ZDF fa/fa and non-diabetic ZDF +/+ rats and stabilized by an internal plate. Saline or 25 mg/kg Scl-AbVI was administered s.c. twice weekly for 12 weeks (n=9-10/group). Bone mass and strength were assessed using pQCT, µCT, and biomechanical testing. Bone histomorphometry was used to assess bone formation, and the filling of the bone defect was analyzed by µCT. RESULTS: Diabetic rats displayed lower spinal and femoral bone mass compared to non-diabetic rats, and Scl-AbVI treatment significantly enhanced bone mass of the femur and the spine of diabetic rats (p < 0.0001). Scl-AbVI also reversed the deficit in bone strength in the diabetic rats, with 65% and 89% increases in maximum load at the femoral shaft and neck, respectively (p < 0.0001). The lower bone mass in diabetic rats was associated with a 65% decrease in vertebral bone formation rate, which Scl-AbVI increased by 6-fold, consistent with a pronounced anabolic effect. While non-diabetic rats filled 57% of the femoral defect, diabetic rats filled only 21% (p < 0.05). Scl-AbVI treatment increased defect regeneration by 47% and 74%, respectively (p < 0.05). CONCLUSION: Sclerostin antibody treatment reverses the adverse effects of type 2 diabetes mellitus on bone mass and strength, and improves bone defect regeneration in rats. © 2012 American Society for Bone and Mineral Research.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2012; · 6.04 Impact Factor -
Article: Quantitative proteomics reveals novel functions of osteoclast-associated receptor in STAT signaling and cell adhesion in human endothelial cells.
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ABSTRACT: Previous studies indicate a novel role for the osteoclast-associated receptor (OSCAR) in oxidative stress-mediated atherogenesis. However, the functional role of OSCAR in endothelial cells is unknown. Here we characterized OSCAR signaling in human endothelial cells using a proteomic approach. OSCAR was either overexpressed or silenced, and the functional effects were assessed by an in-depth proteomic study using stable isotope labeling with amino acids in cell culture (SILAC). Reduction of complexity using subcellular protein fractions from the membrane, the cytosol, and the nucleus of human endothelial cells enabled the detection of 4975 unique proteins. Of these proteins, OSCAR overexpression regulated 145 and OSCAR silencing regulated 110. These proteins were mainly involved in cellular proliferation, inflammatory response and cell-to-cell signaling. Interestingly, OSCAR modulation reciprocally regulated signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3). Thus, STAT1 and several interferon-induced proteins showed a clear inverse correlation to OSCAR expression, which was further verified by Western blot analysis. In contrast, it was found that OSCAR overexpression activated STAT3. Furthermore, OSCAR overexpression increased proteins involved in cell adhesion, which correlated with an increased adhesion of monocytes to the endothelium after OSCAR overexpression. In conclusion, using a comprehensive proteomic approach, endothelial cell-derived OSCAR was found to be involved in the STAT signaling pathway and to affect monocyte adhesion. This indicates a novel role of OSCAR in the vascular-immune cross-talk.Journal of Molecular and Cellular Cardiology 09/2012; · 5.17 Impact Factor
