Activating transcription factor-4 promotes mineralization in vascular smooth muscle cells

Masuda, Masashi; Miyazaki–Anzai, Shinobu; Keenan, Audrey L.; Shiozaki, Yuji; Okamura, Koji; Chick, Wallace S.; Williams, Kristina; Zhao, Xiaoyun; Rahman, Shaikh Mizanoor; Tintut, Yin; Adams, Christopher M.; Miyazaki, Masaru

doi:10.1172/jci.insight.88646

Cited by 40 publications

(81 citation statements)

References 57 publications

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“…Accordingly, phosphate up-regulates PIT1 expression in VSMCs [ 64 , 84 ]. PIT1 expression can be transcriptionally regulated in VSMCs by several pathways including SAPK/JNK MAP-kinase signaling [ 85 ], β-catenin signaling [ 84 ], or transcription factor-4 (ATF4) [ 86 ]. Activation of the mineralocorticoid receptor (MR) in VSMCs may directly up-regulate PIT1 transcription [ 59 , 66 ].…”

Section: Signaling Pathways Regulating Vsmcs Calcification During Higmentioning

confidence: 99%

Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

Voelkl

Läng

Eckardt

et al. 2019

Cell. Mol. Life Sci.

139

202

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Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.

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Section: Signaling Pathways Regulating Vsmcs Calcification During Higmentioning

confidence: 99%

Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

Voelkl

Läng

Eckardt

et al. 2019

Cell. Mol. Life Sci.

139

202

View full text Add to dashboard Cite

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“…Vascular calcification is a highly regulated process that resembles skeletal bone formation. Some of osteogenesis-related transcription factors, such as Msh homeobox 2 (Msx2), Osx, Runx2 and activating transcription factor 4 (ATF4), are expressed in both calcified medial arterial layers and atherosclerotic plaques [ 126 , 128 , 129 ]. However, the molecular mechanisms by which osteogenic transcription factors promote osteogenic differentiation of vascular smooth muscle cells (VSMCs) or suppress VSMC differentiation still remain unclear.…”

Section: The Mechanisms Of the Medial Vascular Calcification Causementioning

confidence: 99%

“…In addition, the transgenic mice with ApoE deficiency significantly stimulated high-fat diet induced-intimal vascular calcification. A new finding in this study is that ATF4 transcriptionally stimulates expression of type lll sodium-dependent phosphate cotransporters, Pit1 and Pit2, by interacting with CCAAT/enhancer-binding protein beta [ 129 ]. Runx2 is expressed in the early stage of osteoblastogenesis and ATF4 is expressed in the late stage of osteoblastogenesis.…”

Section: The Mechanisms Of the Medial Vascular Calcification Causementioning

confidence: 99%

“…However, no Runx2 stimulates ATF4 gene expression [ 105 , 135 ]. Therefore, one question remains unanswered that why loss-of-function of ATF4 in VSMCs prevented CKD-induced medial vascular calcification in spite of Runx2 expression remains in ATF4-deficient VSMCs [ 129 ]? Why Vitamin-D-induced medial vascular calcification is improved in VSMC-specific Runx2-deficient mice in spite of ATF4 is expressed in Runx2-deficient VSMCs [ 132 ]?…”

Section: The Mechanisms Of the Medial Vascular Calcification Causementioning

confidence: 99%

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Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder

Sugatani

2018

IJMS

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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.

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“…Previous studies have shown that ER stress contributes to the pathogenesis of vascular calcification and ATF4 plays an important role in this process. (8) in vitro studies using VSMC (vascular smooth muscle cells) showed that the knockdown of ATF4 was responsible for the decrease of mRNA levels of PiT1 and PiT2. (9) The relevance of ATF4 and PiT1 in the brain is remarkable, as has already been pointed out, but it is not yet clear what role they play together, especially in relation to cerebral vascular calcifications.It is known that in osteoblastic cellular models (MC3T3-E1), the inactivation of PiT1 or PiT2 does not impair the uptake of Pi by the cell; there is a mechanism of compensation by the transporter that remained activated.…”

mentioning

confidence: 99%

Why Is There No PiT1/SLC20A1 Pathogenic Variants Yet Linked to Primary Familial Brain Calcification?

Santos

Oliveira

2020

Journal of Bone and Mineral Research

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We read with interested the article by Couasnay and colleagues reporting a new role for PiT1 protein, independent of its inorganic phosphate (Pi) transport function, in the regulation and homeostasis of the endoplasmic reticulum (ER) in chondrocytes. (1) The authors showed that PiT1 is necessary for the maintenance, differentiation, and survival of chondrocytes in the growth plate during endochondral ossification. PiT1 protein is encoded by SLC20A1 gene, which, together with PiT2, encoded by SLC20A2, comprises the type III family of sodium-dependent inorganic phosphate transporters, a branch of the solute carrier (SLC) superfamily.According to the PubMed database, in recent years, we have seen an increase in publications involving these two transporters. This increase, which began in 2012, coincides with the publication of the first related gene to Primary Familial Brain Calcification (PFBC), the SLC20A2. (2) Variants in SLC20A2 gene are among the leading causes of PFBC, a rare neuropsychiatric disease, characterized by the presence of abnormal calcium deposits in the brain with bilateral pattern in areas such as the basal ganglia and thalamus. (3) Beyond SLC20A2, so far, variants in four other genes have been identified as causing PFBC: PDGFRβ, PDGFβ, XPR1, and MYORG. (3) PiT1 and PiT2 have a similar distribution in the brains of humans and mice, are localized in neurons, glial cells, and endothelial vascular cells, share the function of importing Pi into the cell, and have high amino acid homology. (4) In view of this, it is intriguing to note that has not yet been reported any variants of SLC20A1 in patients with PFBC. Until now, no research group reported families with PFBC were linked to SLC20A1 variants, including ours, despite active screening in patients excluded for the five previous genes (unpublished data). Although not yet detected in the patients with PFBC, recent studies have identified that variants in SLC20A1 represent a potential risk for other quite distinct diseases, such as vertebral fractures (independent of low bone density) (5) and combined pituitary hormone deficiency. (6) In all of these cases, no brain calcification has been reported.In general, studies show that Pit1 is critical for the maintenance of adhesion and cell proliferation. The inviability of the complete knockout mouse to SLC20A1 shows the importance of this gene for cell maintenance. (7) In addition to that already discussed here, PiT1 is involved in several other functions such as erythropoiesis, increased insulin signaling, decreased hepatic lipogenesis, and regulation of apoptosis induced by TNFα, as is approached by Couasnay and colleagues. (1) Couasnay and colleagues (1) show that in chondrocytes, PiT1 expression is regulated by ATF4, a transcription factor related to the cytoprotection response performed by the ER. In this same work, the authors further suggest that the regulation of PiT1 by ATF4 may reveal roles in other physiological mechanisms. Previous studies have shown that ER stress contributes to the pathogenes...

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Activating transcription factor-4 promotes mineralization in vascular smooth muscle cells

Cited by 40 publications

References 57 publications

Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder

Why Is There No PiT1/SLC20A1 Pathogenic Variants Yet Linked to Primary Familial Brain Calcification?

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