Regulation of vascular smooth muscle cell calcification by syndecan-4/FGF-2/PKCα signalling and cross-talk with TGFβ

Borland, Samantha; Morris, Thomas; Borland, Shona; Morgan, Mark R.; Francis, Sheila; Merry, Catherine L. R.; Canfield, Ann E.

doi:10.1093/cvr/cvx178

Cited by 36 publications

(31 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We show that TGF-β1-induced SMAD2 phosphorylation is increased in PKCα siRNA-treated VSMCs and that extensive phosphorylated SMAD2 expression is detected in calcified aortic arches from PKCα -/mice. As we have previously shown that inhibiting TGF-β receptor signaling with SB431542 prevents the increase in mineralization observed in PKCα siRNA-treated VSMCs in vitro 20 , these data suggest that loss of PKCα increases calcification both in vitro 20,33 and in vivo by upregulating TGF-β/SMAD2 signaling in VSMCs.…”

Section: Discussionsupporting

confidence: 73%

“…Six-micron sections were cut using a Microm HM 355S and dried overnight at 37°C. Tissue sections, every 60 microns, were analyzed for calcification by staining with von Kossa and counterstaining with nuclear fast red 20 . Images were acquired on a 3D-Histech Pannoramic-250 microscope slide-scanner using a 40x/0.95 Plan Apochromat objective (Zeiss).…”

Section: Histologymentioning

confidence: 99%

“…The phenotypic modulation of a subset of vascular smooth muscle cells (VSMCs) has been strongly implicated in this disease process as these cells can differentiate into osteo/chondrogenic-like cells both in vitro [11][12][13][14][15][16] and in vivo 17,18 in response to specific stimuli, resulting in the deposition of a mineralized matrix in the vessel wall. Degradation of elastin in the blood vessel wall has also been shown to occur in uremia and CKD 19 , leading to the over-expression of transforming growth factor-β (TGF-β) which promotes VSMC osteogenic differentiation and matrix mineralisation 20,21 .…”

Section: Introductionmentioning

confidence: 99%

“…However, we recently discovered that biochemical inhibition of PKCα activity using Gö6976, or knockingdown PKCα expression using small interfering RNA (siRNA), increases high phosphate-induced mineral deposition by vascular smooth muscle cells (VSMCs) in vitro 20 ; suggesting that vascular calcification and its devastating consequences could be increased if renal disease patients are treated with PKCα inhibitors.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

Borland

Facchi

Adamson

et al. 2020

Preprint

View full text Add to dashboard Cite

Arterial medial calcification is an independent risk factor for mortality in chronic kidney disease. We previously reported that knock-down of PKCα expression increases high phosphate-induced mineral deposition by vascular smooth muscle cells in vitro. This new study tests the hypothesis that PKCα regulates uremia-induced medial calcification in vivo. Female wild-type and PKCα -/mice underwent a two-stage subtotal nephrectomy and were fed a high phosphate diet for 8 weeks. X-ray micro computed tomography demonstrated that uremia-induced medial calcification was increased in the abdominal aorta and aortic arch of PKCα -/mice compared to wild-types. Blood urea nitrogen was also increased in PKCα -/mice compared to wild-types; there was no correlation between blood urea nitrogen and calcification in PKCα -/mice.Phosphorylated SMAD2 immunostaining was detected in calcified aortic arches from uremic PKCα -/mice; the osteogenic marker Runx2 was also detected in these areas. No phosphorylated SMAD2 staining were detected in calcified arches from uremic wild-types. PKCα knock-down increased TGF-β1-induced SMAD2 phosphorylation in vascular smooth muscle cells in vitro, whereas the PKCα activator prostratin decreased SMAD2 phosphorylation. In conclusion, loss of PKCα increases uremia-induced medial calcification. The PKCα/TGF-β signaling axis could therefore represent a new therapeutic target for arterial medial calcification in chronic kidney disease.

show abstract

Section: Discussionsupporting

confidence: 73%

Section: Histologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

Borland

Facchi

Adamson

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…We observed specific calcified structures in the M‐side of clubfoot for the first time (Figure ). This could bring a direct connection with overexpression of asporin (which plays a role in biomineralization), TGFβip (essential for TGFβ signaling), and the intracellular pool of TGFβ (relationships to collagen calcification) in the M‐side. Moreover Seki et al declared that overexpressed CILP suppressed TFGβ signaling in lumbal disc disease .…”

Section: Discussionmentioning

confidence: 99%

Novel contribution to clubfoot pathogenesis: The possible role of extracellular matrix proteins

Eckhardt

Novotný

Doubková

et al. 2019

Journal Orthopaedic Research

View full text Add to dashboard Cite

Idiopathic pes equinovarus (clubfoot) is a congenital deformity of the feet and lower legs. Clubfoot belongs to a group of fibro‐proliferative disorders but its origin remains unknown. Our study aimed to achieve the first complex proteomic comparison of clubfoot contracted tissue of the foot (medial side; n = 16), with non‐contracted tissue (lateral side; n = 13). We used label‐free mass spectrometry quantification and immunohistochemistry. Seven proteins were observed to be significantly upregulated in the medial side (asporin, collagen type III, V, and VI, versican, tenascin‐C, and transforming growth factor beta induced protein) and four in the lateral side (collagen types XII and XIV, fibromodulin, and cartilage intermediate layer protein 2) of the clubfoot. Comparison of control samples from cadavers brought only two different protein concentrations (collagen types I and VI). We also revealed pathological calcification and intracellular positivity of transforming growth factor beta only in the contracted tissue of clubfoot. Most of the 11 differently expressed proteins are strongly related to the extracellular matrix architecture and we assume that they may play specific roles in the pathogenesis of this deformity. These proteins seem to be promising targets for future investigations and treatment of this disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

show abstract

Dermatologic Adverse Events Associated with Selective Fibroblast Growth Factor Receptor Inhibitors: Overview, Prevention, and Management Guidelines

et al. 2020

View full text Add to dashboard Cite

Fibroblast growth factor receptor (FGFR) tyrosine kinases, which are expressed on the cell membrane, are involved in a wide range of biological functions such as cell proliferation, survival, migration, and differentiation. The identification of FGFR fusions and other alterations in a wide range of solid tumors, including cholangiocarcinoma and bladder cancer, has resulted in the development of several selective FGFR inhibitors for use in these indications, for example, infigratinib, erdafitinib, derazantinib, pemigatinib, and futibatinib. In addition to the typical adverse events associated with tyrosine kinases, the FGFR inhibitors appear to give rise to a number of adverse events affecting the skin. Here we describe these skin events, which include the more common nail adverse events (e.g., onycholysis), palmar-plantar erythrodysesthesia syndrome, and stomatitis, as well as less common reactions such as calciphylaxis. This review aims to provide oncologists with an understanding of these dermatologic events and proposes guidelines for the management of treatment-emergent dermatologic adverse events. Awareness of possible adverse events associated with specific drugs should allow physicians to educate patients as to what to expect and implement effective management plans at the earliest possible opportunity, thereby preventing premature discontinuation while maintaining patient quality of life. The Oncologist 2020;25:1-11 Implications for Practice: Identification of fibroblast growth factor receptor (FGFR) aberrations in cholangiocarcinoma and bladder cancer led to development of selective FGFR inhibitors for these indications, based on clinical benefit and safety profiles. The most frequent adverse events (AEs) include those affecting skin, hair, and nails, a unique class effect of these agents. These are usually mild to moderate in severity. This work reviewed skin AEs reported with FGFR inhibitors and provides management guidelines for physicians, aiming to increase awareness of skin events and provide effective treatment strategies. Early intervention and effective management may improve treatment adherence, optimize outcomes, and improve quality of life.

show abstract

Regulation of vascular smooth muscle cell calcification by syndecan-4/FGF-2/PKCα signalling and cross-talk with TGFβ

Cited by 36 publications

References 42 publications

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

Novel contribution to clubfoot pathogenesis: The possible role of extracellular matrix proteins

Dermatologic Adverse Events Associated with Selective Fibroblast Growth Factor Receptor Inhibitors: Overview, Prevention, and Management Guidelines

Contact Info

Product

Resources

About