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Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder
The high cardiovascular mortality associated with chronic kidney disease (CKD) is caused in part by the CKD-mineral bone disorder (CKD-MBD) syndrome. The CKD-MBD consists of skeletal, vascular and cardiac pathology caused by metabolic derangements produced by kidney disease. The prevalence of osteop...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163495/ https://www.ncbi.nlm.nih.gov/pubmed/30142896 http://dx.doi.org/10.3390/ijms19092490 |
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author | Sugatani, Toshifumi |
author_facet | Sugatani, Toshifumi |
author_sort | Sugatani, Toshifumi |
collection | PubMed |
description | The high cardiovascular mortality associated with chronic kidney disease (CKD) is caused in part by the CKD-mineral bone disorder (CKD-MBD) syndrome. The CKD-MBD consists of skeletal, vascular and cardiac pathology caused by metabolic derangements produced by kidney disease. The prevalence of osteopenia/osteoporosis resulting from the skeletal component of the CKD-MBD, renal osteodystrophy (ROD), in patients with CKD exceeds that of the general population and is a major public health concern. That CKD is associated with compromised bone health is widely accepted, yet the mechanisms underlying impaired bone metabolism in CKD are not fully understood. Therefore, clarification of the molecular mechanisms by which CKD produces ROD is of crucial significance. We have shown that activin A, a member of the transforming growth factor (TGF)-β super family, is an important positive regulator of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis with Smad-mediated signaling being crucial for inducing osteoclast development and function. Recently, we have demonstrated systemic activation of activin receptors and activin A levels in CKD mouse models, such as diabetic CKD and Alport (AL) syndrome. In these CKD mouse models, bone remodeling caused by increased osteoclast numbers and activated osteoclastic bone resorption was observed and treatment with an activin receptor ligand trap repaired CKD-induced-osteoclastic bone resorption and stimulated individual osteoblastic bone formation, irrespective of parathyroid hormone (PTH) elevation. These findings have opened a new field for exploring mechanisms of activin A-enhanced osteoclast formation and function in CKD. Activin A appears to be a strong candidate for CKD-induced high-turnover ROD. Therefore, the treatment with the decoy receptor for activin A might be a good candidate for treatment for CKD-induced osteopenia or osteoporosis, indicating that the new findings from in these studies will lead to the identification of novel therapeutic targets for CKD-related and osteopenia and osteoporosis in general. In this review, we describe the impact of CKD-induced Smad signaling in osteoclasts, osteoblasts and vascular cells in CKD. |
format | Online Article Text |
id | pubmed-6163495 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61634952018-10-10 Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder Sugatani, Toshifumi Int J Mol Sci Review The high cardiovascular mortality associated with chronic kidney disease (CKD) is caused in part by the CKD-mineral bone disorder (CKD-MBD) syndrome. The CKD-MBD consists of skeletal, vascular and cardiac pathology caused by metabolic derangements produced by kidney disease. The prevalence of osteopenia/osteoporosis resulting from the skeletal component of the CKD-MBD, renal osteodystrophy (ROD), in patients with CKD exceeds that of the general population and is a major public health concern. That CKD is associated with compromised bone health is widely accepted, yet the mechanisms underlying impaired bone metabolism in CKD are not fully understood. Therefore, clarification of the molecular mechanisms by which CKD produces ROD is of crucial significance. We have shown that activin A, a member of the transforming growth factor (TGF)-β super family, is an important positive regulator of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis with Smad-mediated signaling being crucial for inducing osteoclast development and function. Recently, we have demonstrated systemic activation of activin receptors and activin A levels in CKD mouse models, such as diabetic CKD and Alport (AL) syndrome. In these CKD mouse models, bone remodeling caused by increased osteoclast numbers and activated osteoclastic bone resorption was observed and treatment with an activin receptor ligand trap repaired CKD-induced-osteoclastic bone resorption and stimulated individual osteoblastic bone formation, irrespective of parathyroid hormone (PTH) elevation. These findings have opened a new field for exploring mechanisms of activin A-enhanced osteoclast formation and function in CKD. Activin A appears to be a strong candidate for CKD-induced high-turnover ROD. Therefore, the treatment with the decoy receptor for activin A might be a good candidate for treatment for CKD-induced osteopenia or osteoporosis, indicating that the new findings from in these studies will lead to the identification of novel therapeutic targets for CKD-related and osteopenia and osteoporosis in general. In this review, we describe the impact of CKD-induced Smad signaling in osteoclasts, osteoblasts and vascular cells in CKD. MDPI 2018-08-23 /pmc/articles/PMC6163495/ /pubmed/30142896 http://dx.doi.org/10.3390/ijms19092490 Text en © 2018 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Sugatani, Toshifumi Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder |
title | Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder |
title_full | Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder |
title_fullStr | Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder |
title_full_unstemmed | Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder |
title_short | Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder |
title_sort | systemic activation of activin a signaling causes chronic kidney disease-mineral bone disorder |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163495/ https://www.ncbi.nlm.nih.gov/pubmed/30142896 http://dx.doi.org/10.3390/ijms19092490 |
work_keys_str_mv | AT sugatanitoshifumi systemicactivationofactivinasignalingcauseschronickidneydiseasemineralbonedisorder |