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. 2026 Mar 9;153(10):769–785. doi: 10.1161/CIRCULATIONAHA.125.072393

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© 2026 The Authors.

Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

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Figure 4. — Schematic of upstream triggers and downstream osteochondrogenic pathways in cardiovascular cells. Mechanisms believed to drive aortic and aortic valve calcification. Pathways shaded in blue are functionally related under the concept of inflammaging. Details are described in the text. As indicated, RUNX2 (runt-related transcription factor 2) appears to be central, leading the final common pathways to bone and cartilage tissue formation, which are not shown. Also not included are some inhibitory factors, such as fetuin and sclerostin. ABCC6 indicates ATP-binding cassette subfamily C member 6; AGE, advanced glycation end product; ALP, alkaline phosphatase; ANK, ankyrin; ATX, autotaxin; BMP, bone morphogenetic protein; c-WNT, canonical Wnt; CKD, chronic kidney disease; CPP, calciprotein particle; ECM, extracellular matrix; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; FGF23, fibroblast growth factor 23; IL-1β, interleukin-1β; IL-6, interleukin-6; IFN, interferon; Lp(a), lipoprotein a; LRP6, low-density lipoprotein receptor-related protein 6; MGP, matrix Gla protein; miRNA, microRNA; nc-WNT, noncanonical Wnt; OPG, osteoprotegerin; OxLDL, oxidized low-density lipoprotein; p-OPN, phosphorylated osteopontin; PPi, inorganic pyrophosphate; PTH, parathyroid hormone; PTHr, parathyroid hormone receptor; RANK, receptor activator of nuclear factor-κΒ; RANKL, receptor activator of nuclear factor-κΒ ligand; ROS, reactive oxygen species; TERT, telomerase reverse transcriptase; TLR3, Toll-like receptor 3; and TNFα, tumor necrosis factor.