Abstract
SummaryBiomineralization 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.
Highlights
Biomineralization is the deposition of mineral particles within a proteinaceous organic matrix
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
We report that biomineralization of bone and the vasculature is associated with extracellular poly(ADP-ribose) synthesized by poly(ADPribose) polymerases in response to oxidative and/or DNA damage
Summary
Biomineralization is the deposition of mineral particles within a proteinaceous organic matrix. In the vasculature, where calcification occurs at two anatomical sites—the vessel intima during atherosclerosis and the vessel media in aging, diabetes, and chronic kidney disease (CKD)—the mineral deposits are typically dystrophic, and a range of substrates can be calcified These include collagen fibrils, though organized mineral akin to that in bone is rarely observed; striated elastin (Shimamura, 1970); and spherical nanostructures (Shimamura, 1970; Bertazzo et al, 2013; Hutcheson et al, 2016) that may originate from cell-derived extracellular vesicles (EVs) (Reynolds et al, 2004; Kapustin et al, 2015). It remains unclear how calcium ions are selectively and
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