BMP2/Smad signaling pathway is involved in the inhibition function of fibroblast growth factor 21 on vascular calcification

Liu, Huan; Cao, Fangying; Liu, Shuang; Mi, Yuhong; Liu, Jinghua

doi:10.1016/j.bbrc.2018.06.098

Cited by 14 publications

(13 citation statements)

References 31 publications

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“…BMP, which exists in various subtypes, signaling is activated through phosphorylation and nuclear translocation of Smad [172]. Among the subtypes, BMP2 is best known for its role in the development of VC [173]. Numerous studies have demonstrated that BMP2 is involved in VC [174], since it contributes to the transdifferentiation of VSMCs into osteochondrogenic cells [175], and BMP2, combined with BMP4, localizes to sites of VC [176].…”

Section: Bone Morphogenic Protein (Bmp)2mentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

258

254

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Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.

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Section: Bone Morphogenic Protein (Bmp)2mentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

258

254

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“…Since phosphate uptake via PIT-1, as well as activation of NF-κB, promotes the expression of BMP2 in VSMCs [ 19 , 58 , 83 ] and the BMP2/p-SMAD pathway is strongly involved in vascular calcification [ 46 , 77 ], we next analysed whether BMP2 expression in vitro and in vivo is modified by CBF. Calcifying conditions caused a strong and significant increase in BMP2 mRNA expression compared to that in cells cultured under non-calcifying conditions, an effect that was reversed when the cells were incubated in the presence of CBF (Fig.…”

Section: Resultsmentioning

confidence: 99%

Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation

et al. 2021

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The adrenal glands participate in cardiovascular (CV) physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function. In the present study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification. This peptide was named the “calcification blocking factor” (CBF) due to its protective effect against vascular calcification and is released from chromogranin A via enzymatic cleavage by calpain 1 and kallikrein. CBF reduced the calcium content of cells and thoracic aortic rings under calcifying culture conditions, as well as in aortas from animals treated with vitamin D and nicotine (VDN animals). Furthermore, CBF prevented vascular smooth muscle cell (VSMC) transdifferentiation into osteoblast-like cells within the vascular wall via the sodium-dependent phosphate transporter PIT-1 and by inhibition of NF-κB activation and the subsequent BMP2/p-SMAD pathway. Pulse pressure, a marker of arterial stiffness, was significantly decreased in VDN animals treated with CBF. In line with our preclinical data, CBF concentration is significantly reduced in diseases characterized by increased calcification, as shown in patients with chronic kidney disease. In preparation for clinical translation, the active site of the native 19-AS long native CBF was identified as EGQEEEED. In conclusion, we have identified the new peptide CBF, which is secreted from the adrenal glands and might prevent vascular calcification by inhibition of osteogenic transdifferentiation. The anti-calcific effects of CBF and short active site may therefore promote the development of new tools for the prevention and/or treatment of vascular calcification.

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“…In vascular smooth muscle cells it has been shown that FGF21 is suppressing bone morphogenic protein-2 (BMP-2) mRNA expression (Cao et al, 2017a; Cao et al, 2017b), which is a potent osteogenic protein required for osteoblast differentiation and bone formation (Cai et al, 2012). FGF21 inhibits osteoblast differentiation and vascular calcification in vitro by the BMP-2/Smad signaling pathway (Liu et al, 2018), and could inhibit the osteogenic differentiation in human bone mesenchymal stem cells (hBMSCs) under hyperglycemic conditions (Li et al, 2016b). Future work could include in vitro studies to further clarify the mechanisms responsible for the effect on bone outlined herein.…”

Section: Discussionmentioning

confidence: 99%

FGF21, not GCN2, influences bone morphology due to dietary protein restrictions

et al. 2020

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BackgroundDietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone.MethodsAdult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (μCT) for changes in trabecular and cortical architecture and mass.ResultsIn WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture.ConclusionsThis study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.

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BMP2/Smad signaling pathway is involved in the inhibition function of fibroblast growth factor 21 on vascular calcification

Cited by 14 publications

References 31 publications

Vascular Calcification—New Insights into Its Mechanism

Vascular Calcification—New Insights into Its Mechanism

Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation

FGF21, not GCN2, influences bone morphology due to dietary protein restrictions

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