TY - JOUR

T1 - The Calcified Vasculature in Chronic Kidney Disease Secretes Factors that Inhibit Bone Mineralization

AU - Mace, Maria L.

AU - Gravesen, Eva

AU - Nordholm, Anders

AU - Egstrand, Soeren

AU - Morevati, Marya

AU - Olgaard, Klaus

AU - Lewin, Ewa

N1 - Publisher Copyright: © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

PY - 2022

Y1 - 2022

N2 - Vascular calcification and bone disorder progress simultaneously in chronic kidney disease (CKD). Still, how the complex pathological mechanisms are linked is only sparsely understood. Up to now, the focus has been on the disturbed bone metabolism in developing vascular calcification. However, our group has recently demonstrated that vascular calcification has negative effects on bone formation and mineralization as shown in the bone of normal recipient rats transplanted with the calcified aorta from CKD rats. In the present in vitro study, the hypothesis of a direct crosstalk between the vasculature and bone was examined. Calcified aortas from 5/6 nephrectomized rats and normal aortas from control rats were excised and incubated ex vivo. The calcified aorta secreted large amounts of sclerostin, dickkopf-1 (Dkk1), and activin A. Both normal and calcified aortas secreted frizzle-related protein 4 (SFRP4). Aorta rings were co-incubated with the osteoblast-like cell line UMR-106. The calcified aorta strongly inhibited calcium crystal formation in UMR-106 cells, together with a significant upregulation of the mineralization inhibitors osteopontin and progressive ankylosis protein homolog (ANKH). The strong stimulation of osteopontin was blocked by lithium chloride, indicating involvement of Wnt/β-catenin signaling. The present in vitro study shows detrimental effects of the calcified aorta on bone cell mineralization. These findings support the hypothesis of an active role of the calcified vasculature in the systemic CKD–mineral and bone disorder (CKD-MBD), resulting in a pathological vascular–bone tissue crosstalk.

AB - Vascular calcification and bone disorder progress simultaneously in chronic kidney disease (CKD). Still, how the complex pathological mechanisms are linked is only sparsely understood. Up to now, the focus has been on the disturbed bone metabolism in developing vascular calcification. However, our group has recently demonstrated that vascular calcification has negative effects on bone formation and mineralization as shown in the bone of normal recipient rats transplanted with the calcified aorta from CKD rats. In the present in vitro study, the hypothesis of a direct crosstalk between the vasculature and bone was examined. Calcified aortas from 5/6 nephrectomized rats and normal aortas from control rats were excised and incubated ex vivo. The calcified aorta secreted large amounts of sclerostin, dickkopf-1 (Dkk1), and activin A. Both normal and calcified aortas secreted frizzle-related protein 4 (SFRP4). Aorta rings were co-incubated with the osteoblast-like cell line UMR-106. The calcified aorta strongly inhibited calcium crystal formation in UMR-106 cells, together with a significant upregulation of the mineralization inhibitors osteopontin and progressive ankylosis protein homolog (ANKH). The strong stimulation of osteopontin was blocked by lithium chloride, indicating involvement of Wnt/β-catenin signaling. The present in vitro study shows detrimental effects of the calcified aorta on bone cell mineralization. These findings support the hypothesis of an active role of the calcified vasculature in the systemic CKD–mineral and bone disorder (CKD-MBD), resulting in a pathological vascular–bone tissue crosstalk.

KW - ACTIVIN A

KW - CKD-MBD

KW - RENAL OSTEODYSTROPHY

KW - TISSUE CROSSTALK

KW - WNT INHIBITORS

UR - http://www.scopus.com/inward/record.url?scp=85125503123&partnerID=8YFLogxK

U2 - 10.1002/jbm4.10610

DO - 10.1002/jbm4.10610

M3 - Journal article

C2 - 35434452

AN - SCOPUS:85125503123

VL - 6

JO - JBMR Plus

JF - JBMR Plus

SN - 2473-4039

IS - 4

M1 - e10610

ER -