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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.
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 StyleBritt 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 StyleBritt 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.
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.
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 StyleBritt 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 StyleBritt 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.
Arterial media calcification is frequently seen in elderly and patients with chronic kidney disease (CKD), diabetes and osteoporosis. Pyrophosphate is a well-known calcification inhibitor that binds to nascent hydroxyapatite crystals and prevents further incorporation of inorganic phosphate into these crystals. However, the enzyme tissue-nonspecific alkaline phosphatase (TNAP), which is expressed in calcified arteries, degrades extracellular pyrophosphate into phosphate ions, by which pyrophosphate loses its ability to block vascular calcification. Here, we aimed to evaluate whether pharmacological TNAP inhibition is able to prevent the development of arterial calcification in a rat model of warfarin-induced vascular calcification. To investigate the effect of the pharmacological TNAP inhibitor SBI-425 on vascular calcification and bone metabolism, a 0.30% warfarin rat model was used. Warfarin exposure resulted in distinct calcification in the aorta and peripheral arteries. Daily administration of the TNAP inhibitor SBI-425 (10 mg/kg/day) for 7 weeks significantly reduced vascular calcification as indicated by a significant decrease in calcium content in the aorta (vehicle 3.84 ± 0.64 mg calcium/g wet tissue vs TNAP inhibitor 0.70 ± 0.23 mg calcium/g wet tissue) and peripheral arteries and a distinct reduction in area % calcification on Von Kossa stained aortic sections as compared to vehicle. Administration of SBI-425 resulted in decreased bone formation rate and mineral apposition rate, and increased osteoid maturation time and this without significant changes in osteoclast- and eroded perimeter. Administration of TNAP inhibitor SBI-425 significantly reduced the calcification in the aorta and peripheral arteries of a rat model of warfarin-induced vascular calcification. However, suppression of TNAP activity should be limited in order to maintain adequate physiological bone mineralization.
Britt Opdebeeck; Ellen Neven; José Luis Millán; Anthony B. Pinkerton; Patrick C. D'Haese; Anja Verhulst. Pharmacological TNAP inhibition efficiently inhibits arterial media calcification in a warfarin rat model but deserves careful consideration of potential physiological bone formation/mineralization impairment. Bone 2020, 137, 115392 .
AMA StyleBritt Opdebeeck, Ellen Neven, José Luis Millán, Anthony B. Pinkerton, Patrick C. D'Haese, Anja Verhulst. Pharmacological TNAP inhibition efficiently inhibits arterial media calcification in a warfarin rat model but deserves careful consideration of potential physiological bone formation/mineralization impairment. Bone. 2020; 137 ():115392.
Chicago/Turabian StyleBritt Opdebeeck; Ellen Neven; José Luis Millán; Anthony B. Pinkerton; Patrick C. D'Haese; Anja Verhulst. 2020. "Pharmacological TNAP inhibition efficiently inhibits arterial media calcification in a warfarin rat model but deserves careful consideration of potential physiological bone formation/mineralization impairment." Bone 137, no. : 115392.
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.
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 StyleBritt 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 StyleBritt 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.
Arterial media calcification refers to ectopic mineralization in the arterial wall and favors arterial stiffness and cardiovascular events. Patients with chronic kidney disease (CKD), diabetes or osteoporosis are highly vulnerable to the development of arterial media calcifications. Tissue non‐specific alkaline phosphatase (TNAP) is upregulated in calcified arteries and plays a key role in the degradation of the calcification inhibitor pyrophosphate into inorganic phosphate ions. A recent study published in The Journal of Pathology showed that an oral dosage of 10 or 30 mg/kg/day SBI‐425, a selective TNAP‐inhibitor, inhibited the development of arterial media calcification in mice suffering from CKD, without affecting bone mineralization. Their results indicated that SBI‐425 is an effective and safe treatment for arterial media calcification. However, additional studies regarding the effect of TNAP‐inhibitor SBI‐425 on the progression and even the reversion of pre‐existing pathological arterial media calcifications without affecting physiological bone mineralization are deserved. Furthermore, investigating the extent to which SBI‐425 inhibits arterial calcification in a non‐CKD context would be of particular interest to treat this co‐morbidity in diabetes and osteoporosis patients. This article is protected by copyright. All rights reserved.
Britt Opdebeeck; Patrick C D'haese; Anja Verhulst. Inhibition of tissue non‐specific alkaline phosphatase; a novel therapy against arterial media calcification? The Journal of Pathology 2019, 250, 248 -250.
AMA StyleBritt Opdebeeck, Patrick C D'haese, Anja Verhulst. Inhibition of tissue non‐specific alkaline phosphatase; a novel therapy against arterial media calcification? The Journal of Pathology. 2019; 250 (3):248-250.
Chicago/Turabian StyleBritt Opdebeeck; Patrick C D'haese; Anja Verhulst. 2019. "Inhibition of tissue non‐specific alkaline phosphatase; a novel therapy against arterial media calcification?" The Journal of Pathology 250, no. 3: 248-250.
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.
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 StyleAnnelies 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 StyleAnnelies 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.
BackgroundProtein-bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) have been associated with cardiovascular morbidity and mortality in patients with CKD. However, direct evidence for a role of these toxins in CKD-related vascular calcification has not been reported.MethodsTo study early and late vascular alterations by toxin exposure, we exposed CKD rats to vehicle, IS (150 mg/kg per day), or PCS (150 mg/kg per day) for either 4 days (short-term exposure) or 7 weeks (long-term exposure). We also performed unbiased proteomic analyses of arterial samples coupled to functional bioinformatic annotation analyses to investigate molecular signaling events associated with toxin-mediated arterial calcification.ResultsLong-term exposure to either toxin at serum levels similar to those experienced by patients with CKD significantly increased calcification in the aorta and peripheral arteries. Our analyses revealed an association between calcification events, acute-phase response signaling, and coagulation and glucometabolic signaling pathways, whereas escape from toxin-induced calcification was linked with liver X receptors and farnesoid X/liver X receptor signaling pathways. Additional metabolic linkage to these pathways revealed that IS and PCS exposure engendered a prodiabetic state evidenced by elevated resting glucose and reduced GLUT1 expression. Short-term exposure to IS and PCS (before calcification had been established) showed activation of inflammation and coagulation signaling pathways in the aorta, demonstrating that these signaling pathways are causally implicated in toxin-induced arterial calcification.ConclusionsIn CKD, both IS and PCS directly promote vascular calcification via activation of inflammation and coagulation pathways and were strongly associated with impaired glucose homeostasis.
Britt Opdebeeck; Stuart Maudsley; Abdelkrim Azmi; Annelies De Maré; Wout De Leger; Bjorn Meijers; Anja Verhulst; Pieter Evenepoel; Patrick C. D’Haese; Ellen Neven. Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance. Journal of the American Society of Nephrology 2019, 30, 751 -766.
AMA StyleBritt Opdebeeck, Stuart Maudsley, Abdelkrim Azmi, Annelies De Maré, Wout De Leger, Bjorn Meijers, Anja Verhulst, Pieter Evenepoel, Patrick C. D’Haese, Ellen Neven. Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance. Journal of the American Society of Nephrology. 2019; 30 (5):751-766.
Chicago/Turabian StyleBritt Opdebeeck; Stuart Maudsley; Abdelkrim Azmi; Annelies De Maré; Wout De Leger; Bjorn Meijers; Anja Verhulst; Pieter Evenepoel; Patrick C. D’Haese; Ellen Neven. 2019. "Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance." Journal of the American Society of Nephrology 30, no. 5: 751-766.