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Anja Verhulst
Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium

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Journal article
Published: 26 July 2021 in Pharmaceutics
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Patients with chronic kidney disease (CKD) suffer from arterial media calcification and a disturbed bone metabolism. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes the calcification inhibitor pyrophosphate (PPi) into inorganic phosphate (Pi) and thereby stimulates arterial media calcification as well as physiological bone mineralization. This study investigates whether the TNAP inhibitor SBI-425, PPi or the combination of both inhibit arterial media calcification in an 0.75% adenine rat model of CKD. Treatments started with the induction of CKD, including (i) rats with normal renal function (control diet) treated with vehicle and CKD rats treated with either (ii) vehicle, (iii) 10 mg/kg/day SBI-425, (iv) 120 µmol/kg/day PPi and (v) 120 µmol/kg/day PPi and 10 mg/kg/day SBI-425. All CKD groups developed a stable chronic renal failure reflected by hyperphosphatemia, hypocalcemia and high serum creatinine levels. CKD induced arterial media calcification and bone metabolic defects. All treatments, except for SBI-425 alone, blocked CKD-related arterial media calcification. More important, SBI-425 alone and in combination with PPi increased osteoid area pointing to a less efficient bone mineralization. Clearly, potential side effects on bone mineralization will need to be assessed in any clinical trial aimed at modifying the Pi/PPi ratio in CKD patients who already suffer from a compromised bone status.

ACS Style

Britt Opdebeeck; Ellen Neven; José Millán; Anthony Pinkerton; Patrick D’Haese; Anja Verhulst. Chronic Kidney Disease-Induced Arterial Media Calcification in Rats Prevented by Tissue Non-Specific Alkaline Phosphatase Substrate Supplementation Rather Than Inhibition of the Enzyme. Pharmaceutics 2021, 13, 1138 .

AMA Style

Britt Opdebeeck, Ellen Neven, José Millán, Anthony Pinkerton, Patrick D’Haese, Anja Verhulst. Chronic Kidney Disease-Induced Arterial Media Calcification in Rats Prevented by Tissue Non-Specific Alkaline Phosphatase Substrate Supplementation Rather Than Inhibition of the Enzyme. Pharmaceutics. 2021; 13 (8):1138.

Chicago/Turabian Style

Britt Opdebeeck; Ellen Neven; José Millán; Anthony Pinkerton; Patrick D’Haese; Anja Verhulst. 2021. "Chronic Kidney Disease-Induced Arterial Media Calcification in Rats Prevented by Tissue Non-Specific Alkaline Phosphatase Substrate Supplementation Rather Than Inhibition of the Enzyme." Pharmaceutics 13, no. 8: 1138.

Review
Published: 15 October 2020 in International Journal of Molecular Sciences
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Arterial calcification, the deposition of calcium-phosphate crystals in the extracellular matrix, resembles physiological bone mineralization. It is well-known that extracellular nucleotides regulate bone homeostasis raising an emerging interest in the role of these molecules on arterial calcification. The purinergic independent pathway involves the enzymes ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs), ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), 5′-nucleotidase and alkaline phosphatase. These regulate the production and breakdown of the calcification inhibitor—pyrophosphate and the calcification stimulator—inorganic phosphate, from extracellular nucleotides. Maintaining ecto-nucleotidase activities in a well-defined range is indispensable as enzymatic hyper- and hypo-expression has been linked to arterial calcification. The purinergic signaling dependent pathway focusses on the activation of purinergic receptors (P1, P2X and P2Y) by extracellular nucleotides. These receptors influence arterial calcification by interfering with the key molecular mechanisms underlying this pathology, including the osteogenic switch and apoptosis of vascular cells and possibly, by favoring the phenotypic switch of vascular cells towards an adipogenic phenotype, a recent, novel hypothesis explaining the systemic prevention of arterial calcification. Selective compounds influencing the activity of ecto-nucleotidases and purinergic receptors, have recently been developed to treat arterial calcification. However, adverse side-effects on bone mineralization are possible as these compounds reasonably could interfere with physiological bone mineralization.

ACS Style

Britt Opdebeeck; Isabel R. Orriss; Ellen Neven; Patrick C. D’Haese; Anja Verhulst. Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways. International Journal of Molecular Sciences 2020, 21, 7636 .

AMA Style

Britt Opdebeeck, Isabel R. Orriss, Ellen Neven, Patrick C. D’Haese, Anja Verhulst. Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways. International Journal of Molecular Sciences. 2020; 21 (20):7636.

Chicago/Turabian Style

Britt Opdebeeck; Isabel R. Orriss; Ellen Neven; Patrick C. D’Haese; Anja Verhulst. 2020. "Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways." International Journal of Molecular Sciences 21, no. 20: 7636.

Review
Published: 30 April 2020 in International Journal of Molecular Sciences
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Sclerostin, a 22-kDa glycoprotein that is mainly secreted by the osteocytes, is a soluble inhibitor of canonical Wnt signaling. Therefore, when present at increased concentrations, it leads to an increased bone resorption and decreased bone formation. Serum sclerostin levels are known to be increased in the elderly and in patients with chronic kidney disease. In these patient populations, there is a high incidence of ectopic cardiovascular calcification. These calcifications are strongly associated with cardiovascular morbidity and mortality. Although data are still controversial, it is likely that there is a link between ectopic calcification and serum sclerostin levels. The main question, however, remains whether sclerostin exerts either a protective or deleterious role in the ectopic calcification process.

ACS Style

Annelies De Maré; Patrick C. D’Haese; Anja Verhulst. The Role of Sclerostin in Bone and Ectopic Calcification. International Journal of Molecular Sciences 2020, 21, 3199 .

AMA Style

Annelies De Maré, Patrick C. D’Haese, Anja Verhulst. The Role of Sclerostin in Bone and Ectopic Calcification. International Journal of Molecular Sciences. 2020; 21 (9):3199.

Chicago/Turabian Style

Annelies De Maré; Patrick C. D’Haese; Anja Verhulst. 2020. "The Role of Sclerostin in Bone and Ectopic Calcification." International Journal of Molecular Sciences 21, no. 9: 3199.

Review
Published: 19 January 2020 in Toxins
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The protein-bound uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are considered to be harmful vascular toxins. Arterial media calcification, or the deposition of calcium phosphate crystals in the arteries, contributes significantly to cardiovascular complications, including left ventricular hypertrophy, hypertension, and impaired coronary perfusion in the elderly and patients with chronic kidney disease (CKD) and diabetes. Recently, we reported that both IS and PCS trigger moderate to severe calcification in the aorta and peripheral vessels of CKD rats. This review describes the molecular and cellular mechanisms by which these uremic toxins induce arterial media calcification. A complex interplay between inflammation, coagulation, and lipid metabolism pathways, influenced by epigenetic factors, is crucial in IS/PCS-induced arterial media calcification. High levels of glucose are linked to these events, suggesting that a good balance between glucose and lipid levels might be important. On the cellular level, effects on endothelial cells, which act as the primary sensors of circulating pathological triggers, might be as important as those on vascular smooth muscle cells. Endothelial dysfunction, provoked by IS and PCS triggered oxidative stress, may be considered a key event in the onset and development of arterial media calcification. In this review a number of important outstanding questions such as the role of miRNA’s, phenotypic switching of both endothelial and vascular smooth muscle cells and new types of programmed cell death in arterial media calcification related to protein-bound uremic toxins are put forward and discussed.

ACS Style

Britt Opdebeeck; Patrick C. D’Haese; Anja Verhulst. Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate. Toxins 2020, 12, 58 .

AMA Style

Britt Opdebeeck, Patrick C. D’Haese, Anja Verhulst. Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate. Toxins. 2020; 12 (1):58.

Chicago/Turabian Style

Britt Opdebeeck; Patrick C. D’Haese; Anja Verhulst. 2020. "Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate." Toxins 12, no. 1: 58.

Journal article
Published: 20 November 2019 in Journal of Clinical Medicine
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Mounting evidence indicates that sclerostin, a well-known inhibitor of bone formation, may qualify as a clinically relevant biomarker of chronic kidney disease-related mineral and bone disorder (CKD-MBD), including abnormal mineral and bone metabolism and extraskeletal calcification. For this purpose, in this study we investigate the extent to which circulating sclerostin, skeletal sclerostin expression, bone histomorphometric parameters, and serum markers of bone metabolism associate with each other. Bone biopsies and serum samples were collected in a cohort of 68 end-stage kidney disease (ESKD) patients. Serum sclerostin levels were measured using 4 different commercially available assays. Skeletal sclerostin expression was evaluated on immunohistochemically stained bone sections. Quantitative bone histomorphometry was performed on Goldner stained tissue sections. Different serum markers of bone metabolism were analyzed using in-house techniques or commercially available assays. Despite large inter-assay differences for circulating sclerostin, results obtained with the 4 assays under study closely correlated with each other, whilst moderate significant correlations with skeletal sclerostin expression were also found. Both skeletal and circulating sclerostin negatively correlated with histomorphometric bone and serum parameters reflecting bone formation and turnover. In this study, the unique combined evaluation of bone sclerostin expression, bone histomorphometry, bone biomarkers, and serum sclerostin levels, as assessed by 4 different assays, demonstrated that sclerostin may qualify as a clinically relevant marker of disturbed bone metabolism in ESKD patients.

ACS Style

Annelies De Maré; Anja Verhulst; Etienne Cavalier; Pierre Delanaye; Geert J. Behets; Bjorn Meijers; Dirk Kuypers; Patrick C. D’Haese; Pieter Evenepoel; Maré; D’ Haese. Clinical Inference of Serum and Bone Sclerostin Levels in Patients with End-Stage Kidney Disease. Journal of Clinical Medicine 2019, 8, 2027 .

AMA Style

Annelies De Maré, Anja Verhulst, Etienne Cavalier, Pierre Delanaye, Geert J. Behets, Bjorn Meijers, Dirk Kuypers, Patrick C. D’Haese, Pieter Evenepoel, Maré, D’ Haese. Clinical Inference of Serum and Bone Sclerostin Levels in Patients with End-Stage Kidney Disease. Journal of Clinical Medicine. 2019; 8 (12):2027.

Chicago/Turabian Style

Annelies De Maré; Anja Verhulst; Etienne Cavalier; Pierre Delanaye; Geert J. Behets; Bjorn Meijers; Dirk Kuypers; Patrick C. D’Haese; Pieter Evenepoel; Maré; D’ Haese. 2019. "Clinical Inference of Serum and Bone Sclerostin Levels in Patients with End-Stage Kidney Disease." Journal of Clinical Medicine 8, no. 12: 2027.

Journal article
Published: 21 July 2019 in Toxins
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Sclerostin is a well-known inhibitor of bone formation that acts on Wnt/β-catenin signaling. This manuscript considers the possible role of sclerostin in vascular calcification, a process that shares many similarities with physiological bone formation. Rats were exposed to a warfarin-containing diet to induce vascular calcification. Vascular smooth muscle cell transdifferentiation, vascular calcification grade, and bone histomorphometry were examined. The presence and/or production of sclerostin was investigated in serum, aorta, and bone. Calcified human aortas were investigated to substantiate clinical relevance. Warfarin-exposed rats developed vascular calcifications in a time-dependent manner which went along with a progressive increase in serum sclerostin levels. Both osteogenic and adipogenic pathways were upregulated in calcifying vascular smooth muscle cells, as well as sclerostin mRNA and protein levels. Evidence for the local vascular action of sclerostin was found both in human and rat calcified aortas. Warfarin exposure led to a mildly decreased bone and mineralized areas. Osseous sclerostin production and bone turnover did not change significantly. This study showed local production of sclerostin in calcified vessels, which may indicate a negative feedback mechanism to prevent further calcification. Furthermore, increased levels of serum sclerostin, probably originating from excessive local production in calcified vessels, may contribute to the linkage between vascular pathology and impaired bone mineralization.

ACS Style

Annelies De Maré; Stuart Maudsley; Abdelkrim Azmi; Jhana O. Hendrickx; Britt Opdebeeck; Ellen Neven; Patrick C D’Haese; Anja Verhulst. Sclerostin as Regulatory Molecule in Vascular Media Calcification and the Bone-Vascular Axis. Toxins 2019, 11, 428 .

AMA Style

Annelies De Maré, Stuart Maudsley, Abdelkrim Azmi, Jhana O. Hendrickx, Britt Opdebeeck, Ellen Neven, Patrick C D’Haese, Anja Verhulst. Sclerostin as Regulatory Molecule in Vascular Media Calcification and the Bone-Vascular Axis. Toxins. 2019; 11 (7):428.

Chicago/Turabian Style

Annelies De Maré; Stuart Maudsley; Abdelkrim Azmi; Jhana O. Hendrickx; Britt Opdebeeck; Ellen Neven; Patrick C D’Haese; Anja Verhulst. 2019. "Sclerostin as Regulatory Molecule in Vascular Media Calcification and the Bone-Vascular Axis." Toxins 11, no. 7: 428.

Review
Published: 21 December 2018 in International Journal of Molecular Sciences
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Over the past decades metformin has been the optimal first-line treatment for type 2 diabetes mellitus (T2DM). Only in the last few years, it has become increasingly clear that metformin exerts benign pleiotropic actions beyond its prescribed use and ongoing investigations focus on a putative beneficial impact of metformin on the kidney. Both acute kidney injury (AKI) and chronic kidney disease (CKD), two major renal health issues, often result in the need for renal replacement therapy (dialysis or transplantation) with a high socio-economic impact for the patients. Unfortunately, to date, effective treatment directly targeting the kidney is lacking. Metformin has been shown to exert beneficial effects on the kidney in various clinical trials and experimental studies performed in divergent rodent models representing different types of renal diseases going from AKI to CKD. Despite growing evidence on metformin as a candidate drug for renal diseases, in-depth research is imperative to unravel the molecular signaling pathways responsible for metformin’s renoprotective actions. This review will discuss the current state-of-the-art literature on clinical and preclinical data, and put forward potential cellular mechanisms and molecular pathways by which metformin ameliorates AKI/CKD.

ACS Style

Raphaëlle Corremans; Benjamin A. Vervaet; Patrick C. D’Haese; Ellen Neven; Anja Verhulst. Metformin: A Candidate Drug for Renal Diseases. International Journal of Molecular Sciences 2018, 20, 42 .

AMA Style

Raphaëlle Corremans, Benjamin A. Vervaet, Patrick C. D’Haese, Ellen Neven, Anja Verhulst. Metformin: A Candidate Drug for Renal Diseases. International Journal of Molecular Sciences. 2018; 20 (1):42.

Chicago/Turabian Style

Raphaëlle Corremans; Benjamin A. Vervaet; Patrick C. D’Haese; Ellen Neven; Anja Verhulst. 2018. "Metformin: A Candidate Drug for Renal Diseases." International Journal of Molecular Sciences 20, no. 1: 42.

Journal article
Published: 01 October 2015 in Pharmacological Research
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It is known that diabetes coincides with an increased risk of osteoporosis. While a disturbed collagen metabolism is proposed as a possible cause, much remains unknown about the enzymes involved and changes in the collagen-derived dipeptides and amino acids. Therefore, we sought to study this intricate pathway and the effect of dipeptidyl peptidase 4 (DPP4) inhibitors. Control and streptozotocin-nicotinamide-induced diabetic rats were treated for 12 weeks with vehicle or sitagliptin, a DPP4 inhibitor (Con/VH, Con/SG, DM/VH and DM/SG). The activities of four key enzymes involved in collagen breakdown were determined in serum (DPP4, matrix metalloproteinase 2 and 9 and prolidase). Dipeptide (Ala-Pro, Gly-Pro, Pro-Pro and Pro-Hyp) and amino acid (Pro and Hyp) concentrations were measured by liquid chromatography coupled to mass spectrometry. We found three-fold higher MMP9 activities in DM/VH than in controls, while in DM/SG this rise was attenuated. MMP2 and prolidase did not differ in the investigated groups. Furthermore, we are the first to report on two-fold higher Ala-Pro and Pro-Pro levels in diabetes compared to controls. In contrast, Pro-Hyp concentrations were lower in diabetes (DM/VH and DM/SG). DPP4 inhibition does not seem to have a direct influence on the collagen metabolism in streptozotocin-nicotinamide-induced diabetic rats. Instead, it probably acts through its effect on osteoprotective substrates. In diabetes, increased MMP9 activities seem to favour the production of Ala-Pro and Pro-Pro containing collagen fragments. The high Pro-Hyp levels in untreated controls might have a bone-stimulating effect. Nevertheless, the biological significance of these dipeptides is not yet clear and should be further investigated.

ACS Style

L. Baerts; Lorenzo Glorie; W. Maho; A. Eelen; A. Verhulst; P. D’Haese; Adrian Covaci; I. De Meester. Potential impact of sitagliptin on collagen-derived dipeptides in diabetic osteoporosis. Pharmacological Research 2015, 100, 336 -340.

AMA Style

L. Baerts, Lorenzo Glorie, W. Maho, A. Eelen, A. Verhulst, P. D’Haese, Adrian Covaci, I. De Meester. Potential impact of sitagliptin on collagen-derived dipeptides in diabetic osteoporosis. Pharmacological Research. 2015; 100 ():336-340.

Chicago/Turabian Style

L. Baerts; Lorenzo Glorie; W. Maho; A. Eelen; A. Verhulst; P. D’Haese; Adrian Covaci; I. De Meester. 2015. "Potential impact of sitagliptin on collagen-derived dipeptides in diabetic osteoporosis." Pharmacological Research 100, no. : 336-340.

Research article
Published: 10 March 2015 in PLOS ONE
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Zoledronic acid, a highly potent nitrogen-containing bisphosphonate used for the treatment of pathological bone loss, is excreted unmetabolized via the kidney if not bound to the bone. In cancer patients receiving high doses of the compound renal excretion may be associated with acute tubular necrosis. The question of how zoledronic acid is internalized by renal tubular cells has not been answered until now. In the current work, using a primary human tubular cell culture system, the pathway of cellular uptake of zoledronic acid (fluorescently/radiolabeled) and its cytotoxicity were investigated. Previous studies in our laboratory have shown that this primary cell culture model consistently mimics the physiological characteristics of molecular uptake/transport of the epithelium in vivo. Zoledronic acid was found to be taken up by tubular cells via fluid-phase-endocytosis (from apical and basolateral side) as evidenced by its co-localization with dextran. Cellular uptake and the resulting intracellular level was twice as high from the apical side compared to the basolateral side. Furthermore, the intracellular zoledronic acid level was found to be dependent on the administered concentration and not saturable. Cytotoxic effects however, were only seen at higher administration doses and/or after longer incubation times. Although zoledronic acid is taken up by tubular cells, no net tubular transport could be measured. It is concluded that fluid-phase-endocytosis of zoledronic acid and cellular accumulation at high doses may be responsible for the acute tubular necrosis observed in some cancer patients receiving high doses of the compound.

ACS Style

Anja Verhulst; Shuting Sun; Charles E. McKenna; Patrick C. D’Haese. Endocytotic Uptake of Zoledronic Acid by Tubular Cells May Explain Its Renal Effects in Cancer Patients Receiving High Doses of the Compound. PLOS ONE 2015, 10, e0121861 -e0121861.

AMA Style

Anja Verhulst, Shuting Sun, Charles E. McKenna, Patrick C. D’Haese. Endocytotic Uptake of Zoledronic Acid by Tubular Cells May Explain Its Renal Effects in Cancer Patients Receiving High Doses of the Compound. PLOS ONE. 2015; 10 (3):e0121861-e0121861.

Chicago/Turabian Style

Anja Verhulst; Shuting Sun; Charles E. McKenna; Patrick C. D’Haese. 2015. "Endocytotic Uptake of Zoledronic Acid by Tubular Cells May Explain Its Renal Effects in Cancer Patients Receiving High Doses of the Compound." PLOS ONE 10, no. 3: e0121861-e0121861.