Vascular Bmp–Msx2–Wnt Signaling and Oxidative Stress in Arterial Calcification

Abstract

Studies of fracture repair have revealed that paracrine endothelial-mesenchymal interactions direct bone formation that restores osseous integrity. Angiogenic growth factors and specific members of the bone morphogenetic protein (BMP) family mediate these interactions. Recently, these same signals have been shown to be critical in the vascular pathobiology of hypertension, diabetes, and atherosclerosis. In the arterial vasculature, mechanical and inflammatory redox signals, characteristic of hypertension and diabetes have emerged as a secretagogues for BMP production-with downstream activation of endothelial NADPH oxidases (Nox). Preliminary data now indicate that the paracrine signals provided by BMP and reactive oxygen species augment aortic myofibroblast Msx2-Wnt signaling and matrix turnover. The net mural response to these stimuli promotes osteogenic differentiation of calcifying vascular cells, moreover, oxidation of vascular LDL cholesterol generates oxysterols that trigger Runx2 activity via hedgehog pathways. Thus, BMP, Wnt, and hedgehog gene expression programs-osteogenic pathways highly familiar to the bone biologist-are elaborated in the arterial vasculature via redox-regulated mechanisms. In the brief review, we recount mounting evidence that points to oxidative stress as a major contributor to the pathobiology of diabetic arterial calcification.

Quercetin Attenuates Warfarin-induced Vascular Calcification in Vitro Independently from Matrix Gla Protein

“…In addition, activated BMP signaling does not preclude inhibition of calcification by quercetin, further supporting a minor role for this pathway (11). Consistent with the above findings, warfarin-induced calcification in VSMCs does not associate with either induction of transcription factor Msx2, which regulates diabetic calcification via the BMP-Msx2 axis (46), or induction of the phosphate transporter PiT-1 and osteopontin, both of which are markers of PKA-dependent calcification (47). Our findings indicate that despite the many common features between physiologic differentiation of osteoblasts and pathologic osteoblastic transformation of VSMCs, these processes show differences that may potentially underlie the "bone-vascular paradox" in which bone loss in osteoporosis is accompanied by VC (50).…”

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

“…46 Runx2 expression has been postulated to be an early step of mineralization for osteoblasts and may represent ectopic osteogenesis when expressed in other cells. [47][48][49] Pit1 and Pit2 mRNA was increased in Kl Ϫ/Ϫ and decreased in Tg-Kl compared with WT mice ( Figure 4A). Klotho deficiency increased Runx2 and decreased the smooth muscle marker SM22, whereas overexpression of Klotho had the opposite effect.…”

Gender differences in sclerostin and clinical characteristics in type 1 diabetes mellitus

“…Arterial wall is the second most extensively calcified structure in the human body, and VC is a complex process involving cellular phenotypic switch from VSMCs to mineralizing osteoblast-like cells. These phenotypic changes permit arterial VSMC migration into the intima where these cells are able to express several osteogenic genes such as the osteoblastic transcription factor, Cbfa1/Runx2, bone morphogenetic protein 2 (BMP2), and Msx2 (a promoter of early osteoblast development) in addition to extracellular matrix and matrix-degrading metalloproteinases (12,13,37). The prevalence of coronary atherosclerosis is similar between patients with T1DM and those with T2DM, with a relatively higher proportion of noncalcified plaques observed in patients with T2DM in comparison with those with T1DM (38).…”

“…A reduced bone formation as a consequence of reduced osteoblast activity has been identified as the mean pathogenetic effect or for low bone mineral density (BMD) in subjects with T1DM (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39). intimal thickening in atherosclerosis, and Wnt/b-catenin signaling is a regulator of VSMC behavior (9).…”

“…van Buchem disease and sclerosteosis, characterized by high bone mass and impaired sclerostin production (11). However, experimental and clinical evidences demonstrated the expression of sclerostin and WNT molecules also in calcifying vascular tissues (12,13). Sclerostin has been localized in the subendothelial layer of aortic intima in human aortic samples of atherosclerosis (14), giving new insights into the association between atherosclerosis and osteoporosis (15), and supporting the hypothesis that osteoporosis and cardiovascular diseases could be, at least in part, the pleiotropic consequences of impaired Wnt signaling.…”