Poly(ADP-Ribose) Links the DNA Damage Response and Biomineralization

Abstract

Summary Biomineralization of the extracellular matrix is an essential, regulated process. Inappropriate mineralization of bone and the vasculature has devastating effects on patient health, yet an integrated understanding of the chemical and cell biological processes that lead to mineral nucleation remains elusive. Here, we report that biomineralization of bone and the vasculature is associated with extracellular poly(ADP-ribose) synthesized by poly(ADP-ribose) polymerases in response to oxidative and/or DNA damage. We use ultrastructural methods to show poly(ADP-ribose) can form both calcified spherical particles, reminiscent of those found in vascular calcification, and biomimetically calcified collagen fibrils similar to bone. Importantly, inhibition of poly(ADP-ribose) biosynthesis in vitro and in vivo inhibits biomineralization, suggesting a therapeutic route for the treatment of vascular calcifications. We conclude that poly(ADP-ribose) plays a central chemical role in both pathological and physiological extracellular matrix calcification.

Vascular Calcification—New Insights into Its Mechanism

“…In turn, induced apoptosis generates oxidative stress, further mitochondrial dysfunction, apoptotic bodies, and MVs [135][136][137][138], events that have been mechanistically linked to DNA damage, ER stress, autophagy or mitophagy, and calcium phosphate deposition. It can also induce osteogenic gene induction and transformation into osteogenic phenotype of VSMCs [139][140][141][142]. Apoptosis is not mutually exclusive, but actually complementary to other pathways introduced in this review that eventually lead to VC.…”

Molecular mechanisms underlying AMH elevation in hyperoestrogenic states in males

“…The expression of endogenous AMH and the ERα in SMAT1 cells was evaluated by immunofluorescence. After incubation in the dark in a humid chamber for 1 h at room temperature with the corresponding secondary antibody (mouse or rabbit anti-immunoglobulin) coupled to Alexa Fluor ® 488 or Alexa-Fluor ® 594 (Abcam) 98 . Finally, the glasses were mounted with Vectashield (Vector) and sealed with enamel for observation with a Nikon Eclipse E800 microscope and image analysis with ImageJ software 99 .…”

Recent directions in the solid-state NMR study of synthetic and natural calcium phosphates

“…2D 13 C-13 C DQ-SQ, and DARR-assisted 15 N- 13 C correlations) to highlight a number of major features concerning the organic component of bone and the development of the tissue. These include (i) the potential importance of poly-ADP-ribose in the extacellular matrix for developing bone, which is likely to play a role in calcification, [86,88] (ii) the detection in native intact bone of nucleic acids and other low-abundant components (like cholines from phospholipid headgroups, as well as histidinyl and hydroxylysyl groups), [83] and (iii) the in-depth study of collagen structure and flexibility. [79] Organic-mineral interfaces in bone have also been the focus of much attention.…”