Cdon suppresses vascular smooth muscle calcification via repression of the Wnt/Runx2 Axis

Abstract

Osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) is a risk factor associated with vascular diseases. Wnt signaling is one of the major mechanisms implicated in the osteogenic conversion of VSMCs. Since Cdon has a negative effect on Wnt signaling in distinct cellular processes, we sought to investigate the role of Cdon in vascular calcification. The expression of Cdon was significantly downregulated in VSMCs of the aortas of patients with atherosclerosis and aortic stenosis. Consistently, calcification models, including vitamin D3 (VD3)-injected mice and VSMCs cultured with calcifying media, exhibited reduced Cdon expression. Cdon ablation mice (cKO) exhibited exacerbated aortic stiffness and calcification in response to VD3 compared to the controls. Cdon depletion induced the osteogenic conversion of VSMCs accompanied by cellular senescence. The Cdon-deficient aortas showed a significant alteration in gene expression related to cell proliferation and differentiation together with Wnt signaling regulators. Consistently, Cdon depletion or overexpression in VSMCs elevated or attenuated Wnt-reporter activities, respectively. The deletion mutant of the second immunoglobulin domain (Ig2) in the Cdon ectodomain failed to suppress Wnt signaling and osteogenic conversion of VSMCs. Furthermore, treatment with purified recombinant proteins of the entire ectodomain or Ig2 domain of Cdon displayed suppressive effects on Wnt signaling and VSMC calcification. Our results demonstrate a protective role of Cdon in VSMC calcification by suppressing Wnt signaling. The Ig2 domain of Cdon has the potential as a therapeutic tool to prevent vascular calcification.

Vascular Calcification: Molecular Networking, Pathological Implications and Translational Opportunities

“…Norma calcium salts are formed in the ECM rather than intracellular in the intimal layer On the other hand, the structure-function relationship of soft tissue calcification is a very dynamic and intricate process that still requires further understanding. Different cellular types play a role in the process and multiple signaling pathways have been recognized, including Ca 2+ signaling, Wnt/β-catenin, BMP/Smad, and Notch pathways, and different molecular mediators are involved, such as osteogenic factors, growth factors (GFs) or matrix vesicles (MVs) [1,[41][42][43][44][45]. The study of the molecular pathways may drive the exploration of potential therapeutic targets and the use of proper biomarkers.…”

Design Rules for the Nano‐Bio Interface of Nanodiamonds: Implications for siRNA Vectorization

“…Since 2018 introduction of the first siRNA drug Onpattro on market in 2018, [ 8 ] four other siRNA drugs designed for different target mRNAs have been approved by FDA to date: Givlaari (2019), Oxlumo (2020), Leqvio (2021), and Amvuttra (2022). [ 9 ] All these drugs target liver and have been designed for selective treatment of various liver diseases while the other organs are minimally affected. Currently, 68 other RNAi‐based drugs are in clinical trials, [ 5 ] targeting also different organs [ 9 ] and paving thus the way for a wider use of RNAi‐based therapy.…”

“…[ 9 ] All these drugs target liver and have been designed for selective treatment of various liver diseases while the other organs are minimally affected. Currently, 68 other RNAi‐based drugs are in clinical trials, [ 5 ] targeting also different organs [ 9 ] and paving thus the way for a wider use of RNAi‐based therapy.…”