Linking ABCC6 Deficiency in Primary Human Dermal Fibroblasts of PXE Patients to p21-Mediated Premature Cellular Senescence and the Development of a Proinflammatory Secretory Phenotype

Abstract

Pseudoxanthoma elasticum (PXE) is a rare autosomal-recessive disorder that is mainly caused by mutations in the ATP-binding cassette sub-family C member 6 (ABCC6) gene. Clinically PXE is characterized by a loss of skin elasticity, arteriosclerosis or visual impairments. It also shares some molecular characteristics with known premature aging syndromes like the Hutchinson–Gilford progeria syndrome (HGPS). However, little is known about accelerated aging processes, especially on a cellular level for PXE now. Therefore, this study was performed to reveal a potential connection between premature cellular aging and PXE pathogenesis by analyzing cellular senescence, a corresponding secretory phenotype and relevant factors of the cell cycle control in primary human dermal fibroblasts of PXE patients. Here, we could show an increased senescence-associated β-galactosidase (SA-β-Gal) activity as well as an increased expression of proinflammatory factors of a senescence-associated secretory phenotype (SASP) like interleukin 6 (IL6) and monocyte chemoattractant protein-1 (MCP1). We further observed an increased gene expression of the cyclin-dependent kinase inhibitor (CDKI) p21, but no simultaneous induction of p53 gene expression. These data indicate that PXE is associated with premature cellular senescence, which is possibly triggered by a p53-independent p21-mediated mechanism leading to a proinflammatory secretory phenotype.

The Molecular Mechanism of Polyphenols with Anti-Aging Activity in Aged Human Dermal Fibroblasts

“…The senescent cells exhibit increased cell-cycle inhibitors p21 and p16 and increased β-galactosidase activity, loss of nuclear high mobility group box 1 (HMGB1), and decreased lamin B1 [ 8 , 64 ]. These senescent cells produce senescence-associated secretory phenotypes (SASPs) such as pro-inflammatory cytokines and immune modulators [ 65 ]. Because these senescent cells have harmful effects on surrounding cells, recent strategies have aimed at the selective killing of senescent cells (called senolytic) or inhibiting SASPs without affecting the neighbor cells [ 66 ].…”

Serum Calcification Propensity T50 Associates with Disease Severity in Patients with Pseudoxanthoma Elasticum

“…Regarding a possible pathophysiological link between T50 and PXE disease severity, in vitro studies have shown that exposing vascular smooth muscle cells to secondary CPPs provokes a substantial inflammatory and procalcifying reaction, and increases oxidative stress [48,49]. As oxidative stress and increased cytokine production-as part of an overlapping process of excessive DNA damage response and premature senescence-have recently been shown to be involved in PXE pathogenesis, the dose-dependent damaging effects of secondary CPPs (as reflected by T50) might directly link T50 to the molecular process of PXE-related ectopic calcification [32,50].…”

Mitochondrial Dysfunction and Oxidative Stress in Hereditary Ectopic Calcification Diseases

“…In this context, our group and others have recently demonstrated the involvement of excessive DNA damage response (DDR) signaling, mediated via the PARP1-STAT-IL6-RUNX2 axis, in PXE pathogenesis [ 39 , 40 ]. Indeed, overaction of DDR pathways including ATM, p21, and p53 results in premature senescence in PXE fibroblasts and contributes to the EC process [ 39 , 41 ]. On the contrary, PARP1 inhibition by means of minocycline, which is also a known ROS scavenging molecule, significantly reduced EC in both PXE fibroblasts, zebrafish, and mice models [ 39 , 42 ].…”