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The Journal of Investigative Dermatology Jun 2022Pseudoxanthoma elasticum (PXE) is a hereditary ectopic calcification disorder affecting the skin, eyes, and blood vessels. Recently, the DNA damage response (DDR), in...
Pseudoxanthoma elasticum (PXE) is a hereditary ectopic calcification disorder affecting the skin, eyes, and blood vessels. Recently, the DNA damage response (DDR), in particular PARP1, was shown to be involved in aberrant mineralization, raising the hypothesis that excessive DDR/PARP1 signaling also contributes to PXE pathogenesis. Using dermal fibroblasts of patients with PXE and healthy controls, (lesional) skin tissue, and abcc6a zebrafish, we performed expression analysis of DDR/PARP1 targets with QRT-PCR, western blot, immunohistochemistry, and enzyme activity assays before and after treatment with the PARP1 inhibitor minocycline. PARP1 and the ATM‒p21‒p53 axis was found to be significantly increased in PXE. In addition, PARP1 downstream targets IL-6, signal transducer and activator of transcription 1/3, TET1, and RUNX2 were upregulated, whereas the RUNX2 antagonist microRNA-204 was decreased. In PXE fibroblasts, DDR/PARP1 signaling increased with advancing ectopic calcification. Minocycline treatment attenuated DDR/PARP1 overexpression and reduced aberrant mineralization in PXE fibroblasts and abcc6a zebrafish. In summary, we showed the involvement of excessive DDR/PARP1 signaling in PXE pathophysiology, identifying a signal transducer and activator of transcription‒driven cascade resulting in increased expression of the epigenetic modifier TET1 and procalcifying transcription factor RUNX2. Minocycline attenuated this deleterious molecular mechanism and reduced ectopic calcification both in vitro and in vivo, fueling the exciting prospect of a therapeutic compound for PXE.
Topics: ATP-Binding Cassette Transporters; Animals; Core Binding Factor Alpha 1 Subunit; DNA Damage; Humans; MicroRNAs; Minocycline; Mixed Function Oxygenases; Multidrug Resistance-Associated Proteins; Proto-Oncogene Proteins; Pseudoxanthoma Elasticum; Zebrafish; Zebrafish Proteins
PubMed: 34742705
DOI: 10.1016/j.jid.2021.10.019 -
International Journal of Molecular... Dec 2022Ectopic calcification (EC) is characterized by an abnormal deposition of calcium phosphate crystals in soft tissues such as blood vessels, skin, and brain parenchyma. EC... (Review)
Review
Ectopic calcification (EC) is characterized by an abnormal deposition of calcium phosphate crystals in soft tissues such as blood vessels, skin, and brain parenchyma. EC contributes to significant morbidity and mortality and is considered a major health problem for which no effective treatments currently exist. In recent years, growing emphasis has been placed on the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of EC. Impaired mitochondrial respiration and increased levels of reactive oxygen species can be directly linked to key molecular pathways involved in EC such as adenosine triphosphate homeostasis, DNA damage signaling, and apoptosis. While EC is mainly encountered in common diseases such as diabetes mellitus and chronic kidney disease, studies in rare hereditary EC disorders such as pseudoxanthoma elasticum or Hutchinson-Gilford progeria syndrome have been instrumental in identifying the precise etiopathogenetic mechanisms leading to EC. In this narrative review, we describe the current state of the art regarding the role of mitochondrial dysfunction and oxidative stress in hereditary EC diseases. In-depth knowledge of aberrant mitochondrial metabolism and its local and systemic consequences will benefit the research into novel therapies for both rare and common EC disorders.
Topics: Humans; Pseudoxanthoma Elasticum; Progeria; Oxidative Stress; Mitochondria; Reactive Oxygen Species
PubMed: 36499615
DOI: 10.3390/ijms232315288 -
European Journal of Vascular and... Sep 2020
Topics: Arterial Occlusive Diseases; Humans; Iliac Artery; Male; Middle Aged; Pseudoxanthoma Elasticum; Treatment Outcome; Vascular Grafting; Vascular Patency
PubMed: 32723584
DOI: 10.1016/j.ejvs.2020.05.025 -
Postgraduate Medical Journal Feb 1970Eight cases of pseudoxanthoma elasticum seen in a Medical Unit in Singapore are described. Of these six belonged to one family. The clinical presentations of these...
Eight cases of pseudoxanthoma elasticum seen in a Medical Unit in Singapore are described. Of these six belonged to one family. The clinical presentations of these cases, especially the first case who was a diagnostic problem for 5 years, are described. Transmission in this family is autosomal-recessive. Eye changes were absent. Skin lesions were minimal and the axillary folds were more involved than the skin of the neck. Of the eight cases, three were asymptomatic except for cutaneous lesions, three had suffered a haemetemesis and four a haemoptysis, while three had mental changes, and two had cerebrovascular involvement. Case 1 had in addition, bleeding from the nose, urinary tract and uterus. She also had a fatty liver, peripheral neuropathy and hysterical fits. Only one case presented as a cosmetic problem. The pathogenesis of PXE is discussed; the primary defect is believed to be in the elastic and not the collagenous tissue.
Topics: Adult; Aged; Female; Genes, Recessive; Hemorrhage; Humans; Male; Mental Disorders; Middle Aged; Pseudoxanthoma Elasticum; Vascular Diseases
PubMed: 5416513
DOI: 10.1136/pgmj.46.532.97 -
Cureus Jun 2021Pseudoxanthoma elasticum, or Gronblad-Strandberg syndrome, is an inherited disorder that involves multiple organ systems. The characteristic degeneration and...
Pseudoxanthoma elasticum, or Gronblad-Strandberg syndrome, is an inherited disorder that involves multiple organ systems. The characteristic degeneration and calcification of the elastic fibers caused by this disease were first observed by Ferdinand Jean Darrier in 1896. We report a case of a 27-year-old female who was diagnosed with pseudoxanthoma elasticum based on a skin biopsy prior to her presentation to our ophthalmology outpatient clinic. The past ocular history of the patient was unremarkable for any previous eye complaint or surgery. Her ocular and fundus examination showed pigmented grayish irregular post choroidal crack-like linear dehiscence, forming a network-like pattern, originating at the optic disc and extending radially involving the macular area and the posterior pole in both eyes, representing bilateral angioid streaks. There were no clinical or optical coherent tomographic signs of choroidal neovascularization. Periodic follow up for patients with pseudoxanthoma elasticum is recommended to detect choroidal neovascularization which is a sight-threatening complication. Ophthalmologists should be aware of this association as early recognition and treatment are vital to prevent irreversible visual loss.
PubMed: 34277296
DOI: 10.7759/cureus.15720 -
Intractable & Rare Diseases Research May 2023Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease characterized by dystrophic calcification of elastic fibres in the skin, retina and vascular wall....
Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease characterized by dystrophic calcification of elastic fibres in the skin, retina and vascular wall. Data on cardiac involvement are inconsistent. Hence, we aimed to evaluate cardiorespiratory response to incremental cardiopulmonary exercise testing (CPET) in PXE. A total of 30 PXE patients (54.0 ± 11.2 years, 40.0% male) and 15 matched controls underwent symptom-limited incremental CPET. PXE patients presented an impaired peak work rate as compared to controls (84.2 ± 16.0% . 94.7 ± 10.4%, = 0.03) that was accompanied by a lower peak oxygen uptake (in % predicted and mL/min/kg), reduced increments in oxygen uptake per increments of work rate (Δ´O/ΔWR, 8.4 ± 3.0 mL/min/W . 11.3 ± 4.9 mL/ min/W, = 0.02), lower peak oxygen pulse (78.0 ± 12.3% . 90.6 ± 19.6%, = 0.01) and reduced minute ventilation at peak exercise (´E, 66.2 ± 16.8% . 82.9 ± 25.2%, = 0.02). To summarize, we presently observed impairment in mainly cardiocirculatory parameters, whilst no substantial ventilatory limitation was detected. The potential implications of this finding for PXE management warrant further study.
PubMed: 37287659
DOI: 10.5582/irdr.2023.01014 -
International Journal of Molecular... Feb 2022Arterial calcification is a common feature of pseudoxanthoma elasticum (PXE), a disease characterized by mutations, inducing a deficiency in pyrophosphate, a key...
UNLABELLED
Arterial calcification is a common feature of pseudoxanthoma elasticum (PXE), a disease characterized by mutations, inducing a deficiency in pyrophosphate, a key inhibitor of calcium phosphate crystallization in arteries.
METHODS
we analyzed whether long-term exposure of Abcc6 mice (a murine model of PXE) to a mild vitamin D supplementation, with or without calcium, would impact the development of vascular calcification. Eight groups of mice (including Abcc6 and wild-type) received vitamin D supplementation every 2 weeks, a calcium-enriched diet alone (calcium in drinking water), both vitamin D supplementation and calcium-enriched diet, or a standard diet (controls) for 6 months. Aorta and kidney artery calcification was assessed by 3D-micro-computed tomography, Optical PhotoThermal IR (OPTIR) spectroscopy, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS) and Yasue staining.
RESULTS
at 6 months, although vitamin D and/or calcium did not significantly increase serum calcium levels, vitamin D and calcium supplementation significantly worsened aorta and renal artery calcification in Abcc6 mice.
CONCLUSIONS
vitamin D and/or calcium supplementation accelerate vascular calcification in a murine model of PXE. These results sound a warning regarding the use of these supplementations in PXE patients and, to a larger extent, patients with low systemic pyrophosphate levels.
Topics: Animals; Arteries; Calcification, Physiologic; Calcium; Calcium, Dietary; Dietary Supplements; Disease Models, Animal; Female; Mice; Multidrug Resistance-Associated Proteins; Pseudoxanthoma Elasticum; Vascular Calcification; Vitamin D
PubMed: 35216422
DOI: 10.3390/ijms23042302 -
Journal of Medical Genetics Dec 2005Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system. It is characterised... (Review)
Review
Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system. It is characterised pathologically by elastic fibre mineralisation and fragmentation (so called "elastorrhexia"), and clinically by high heterogeneity in age of onset and the extent and severity of organ system involvement. PXE was recently associated with mutations in the ABCC6 (ATP binding cassette subtype C number 6) gene. At least one ABCC6 mutation is found in about 80% of patients. These mutations are identifiable in most of the 31 ABCC6 exons and consist of missense, nonsense, frameshift mutations, or large deletions. No correlation between the nature or location of the mutations and phenotype severity has yet been established. Recent findings support exclusive recessive inheritance. The proposed prevalence of PXE is 1/25,000, but this is probably an underestimate. ABCC6 encodes the protein ABCC6 (also known as MRP6), a member of the large ATP dependent transmembrane transporter family that is expressed predominantly in the liver and kidneys, and only to a lesser extent in tissues affected by PXE. The physiological substrates of ABCC6 remain to be determined, but the current hypothesis is that PXE should be considered to be a metabolic disease with undetermined circulating molecules interacting with the synthesis, turnover, or maintenance of elastic fibres.
Topics: Adenosine Triphosphate; Codon, Nonsense; Exons; Extracellular Matrix; Frameshift Mutation; Gene Deletion; Humans; Models, Genetic; Multidrug Resistance-Associated Proteins; Mutation; Mutation, Missense; Phenotype; Pseudoxanthoma Elasticum; Skin
PubMed: 15894595
DOI: 10.1136/jmg.2004.030171 -
International Journal of Women's... Dec 2021
PubMed: 35028389
DOI: 10.1016/j.ijwd.2021.03.012 -
Atherosclerosis Jun 2022Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by systemic calcification of elastin fibers. Additionally, PXE is associated with an increased risk of...
BACKGROUND AND AIMS
Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by systemic calcification of elastin fibers. Additionally, PXE is associated with an increased risk of stroke. It has been hypothesized that this may be caused by accelerated (intracranial) atherogenesis, as a consequence of specific genetic mutations underlying PXE. Hence, we compared the distribution and burden of intracranial atherosclerosis between PXE patients and healthy controls.
METHODS
Fifty PXE patients and 40 age-and-sex-matched healthy controls (without previous ischemic cerebrovascular disease) underwent 3T MRI to visualize atherosclerotic intracranial vessel wall lesions (VWLs). We compared the presence and burden of VWLs (total and for the anterior cerebral, middle cerebral, intracranial internal carotid, posterior cerebral, and basilar arteries separately) between PXE patients and healthy controls using logistic (presence versus absence) and negative binomial regression models (VWL count) adjusted for relevant confounders. All regressions included group (PXE patients vs. healthy controls) as independent variable.
RESULTS
We found that 34 (68.0%) PXE patients and 28 (70.0%) healthy controls had a VWL (odds ratio for presence 1.06 [95%CI 0.38-2.91]). In addition, the total burden of VWLs was similar between PXE patients (68 VWLs) and healthy controls (73 VWLs, incidence rate ratio for count 0.81 [95%CI 0.55-1.20]). Findings were similar when analyses were stratified for artery.
CONCLUSIONS
The distribution and burden of intracranial atherosclerosis were similar between PXE patients and healthy controls. This implies PXE and its underlying mutations do not involve increased (intracranial) atherogenesis and that vascular calcification or other mechanisms explains the increased stroke risk in PXE.
Topics: Atherosclerosis; Case-Control Studies; Humans; Intracranial Arteriosclerosis; Pseudoxanthoma Elasticum; Stroke; Vascular Calcification
PubMed: 35468517
DOI: 10.1016/j.atherosclerosis.2022.04.014