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Calcifying Human Aortic Smooth Muscle Cells Express Different Bone Alkaline Phosphatase Isoforms, Including the Novel B1x Isoform
Linköping University, Department of Medical and Health Sciences, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
2013 (English)In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 50, no 2, 167-174 p.Article in journal (Refereed) Published
Abstract [en]

Background: Vascular calcification, causing cardiovascular morbidity and mortality, is associated with hyperphosphatemia in chronic kidney disease (CKD). In vitro, phosphate induces transdifferentiation of vascular smooth muscle cells to osteoblast-like cells that express alkaline phosphatase (ALP). In vivo, raised serum ALP activities are associated with increased mortality. A new bone ALP isoform (B1x) has been identified in serum from CKD patients. The present study investigated the different ALP isoforms in calcifying human aortic smooth muscle cells (HAoSMCs). Methods: HAoSMCs were cultured for 30 days in medium containing 5 or 10 mmol/l beta-glycerophosphate in the presence or absence of the ALP-specific inhibitor tetramisole. Results: All known bone-specific ALP (BALP) isoforms (B/I, B1x, B1 and B2) were identified in HAoSMCs. beta-Glycerophosphate stimulated calcification of HAoSMCs, which was associated with increased BALP isoforms B/I, B1x and B2. Tetramisole inhibited the beta-glycerophosphate-induced HAoSMC calcification, which was paralleled by the inhibition of the B1x and B/I, but not the other isoforms. Conclusions: HAoSMCs express the four known BALP isoforms. B/I, B1x and B2 could be essential for soft tissue calcification. B/I and B1x were more affected by tetramisole than the other isoforms, which suggests different biological functions during calcification of HAoSMCs.

Place, publisher, year, edition, pages
S. Karger, 2013. Vol. 50, no 2, 167-174 p.
Keyword [en]
Bone-specific alkaline phosphatase, Chronic kidney disease, Human aortic smooth muscle cells, Isoforms, Phosphate, Vascular calcification
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-90089DOI: 10.1159/000346161ISI: 000314995500008OAI: diva2:612396

Funding Agencies|Ingrid Asps Foundation for Nephrology Research at Linkoping University||County Council of Ostergotland||Swedish Association for Kidney Patients||

Available from: 2013-03-21 Created: 2013-03-19 Last updated: 2014-11-06
In thesis
1. Bone alkaline phosphatase isoforms in chronic kidney disease: mineral and bone disorder
Open this publication in new window or tab >>Bone alkaline phosphatase isoforms in chronic kidney disease: mineral and bone disorder
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic kidney disease (CKD) is associated with increased mortality and cardiovascular complications. Disturbances in mineral metabolism occur early <luring the course of CKD and several components of the CKD-mineral and bone disorder (CKD-MBD) are independent predictors of mortality. Alkaline phosphatase (ALP) is necessary for skeletal mineralization and is also involved in the process of vascular calcification. In recent years, ALP has evolved as a strong predictor of mortality in the CKD population. The significant role of ALP in the mineralization process renders it a putative target for the treatment and prevention of vascular calcification. Three circulating isoforms of bone ALP (BALP) have been identified (B/I, B 1, and B2). A fourth isoform, Blx, has been identified exclusively in serum from patients with CKD. The aim of the present thesis was to further elucidate the role ofthe BALP isoforms in CKD with respect to bone abnormalities and vascular calcification.

In study I we identified the novel BALP isoform Blx in 20% of patients with mild to moderate CKD. Blx was associated with lower glomerular filtration rate and higher serum phosphate and calcium x phosphate product, which are risk factors for cardiovascular mortality in CKD. We also identified the BALP isoforms B/I, Bl and B2 as predictors of total hip bone mineral density.

Study II was an experimental study, investigating the role of the BALP isoforms in phosphate induced calcification of human aortic smooth muscle cells (HASMCs). We found that the ALP expressed in HASMCs is exclusively BALP. Phosphate induced calcification of HASMCs was associated with increased BALP isoforms B/I, Blx, and B2 activities, which implies functional differences between the BALP isoforms in HASMC calcification.

In study III we investigated the association of BALP isoforms in serum and histomorphometric parameters of bone in patients on chronic hemodialysis. W e identified the BALP isoform Blx as a novel marker for reduced osteoblastic activity.

Study IV was a prospective cohort study of the association of serum BALP isoforms with aortic calcification and vascular stiffness in prevalent chronic dialysis patients. Blx was associated with baseline and time varying vascular stiffness, determined by pulse wave velocity, but not with calcification of the abdominal aorta. We also found an association of Blx with better event-free survival.

In conclusion, these studies demonstrate that the BALP isoforms, especially isoform Blx, are involved in different aspects of CKD-MBD. This opens up for further research to identify the BALP isoforms as diagnostic markers and possible treatment targets in CKD-MBD.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 89 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1427
National Category
Clinical Medicine
urn:nbn:se:liu:diva-111870 (URN)10.3384/diss.diva-111870 (DOI)978-91-7519-204-8 (print) (ISBN)
Public defence
2014-11-21, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2014-11-06 Created: 2014-11-06 Last updated: 2015-06-08Bibliographically approved

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Haarhaus, MathiasArnqvist, HansMagnusson, Per
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NephrologyFaculty of Health SciencesDepartment of Nephrology UHLCell BiologyDepartment of EndocrinologyClinical ChemistryDepartment of Clinical Chemistry
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