The regulation of valvular and vascular sclerosis by osteogenic morphogens

Abstract

Vascular calcification increasingly afflicts our aging, dysmetabolic population. Once considered only a passive process of dead and dying cells, vascular calcification has now emerged as a highly regulated form of biomineralization organized by collagenous and elastin extracellular matrices. During skeletal bone formation, paracrine epithelial-mesenchymal and endothelial-mesenchymal interactions control osteochondrocytic differentiation of multipotent mesenchymal progenitor cells. These paracrine osteogenic signals, mediated by potent morphogens of the bone morphogenetic protein and wingless-type MMTV integration site family member (Wnt) superfamilies, are also active in the programming of arterial osteoprogenitor cells during vascular and valve calcification. Inflammatory cytokines, reactive oxygen species, and oxylipids-increased in the clinical settings of atherosclerosis, diabetes, and uremia that promote arteriosclerotic calcification-elicit the ectopic vascular activation of osteogenic morphogens. Specific extracellular and intracellular inhibitors of bone morphogenetic protein-Wnt signaling have been identified as contributing to the regulation of osteogenic mineralization during development and disease. These inhibitory pathways and their regulators afford the development of novel therapeutic strategies to prevent and treat valve and vascular sclerosis.

Figure 1. The relationship of chondrocyte and osteoblast lineages to skeletal and vascular osteoprogenitors

During normal skeletal development, neural crest, mesenchymal stem cells, and bone marrow stromal cells provide abundant sources of osteoprogenitors. Osteochondrocytic differentiation, temporally and spatially regulated by multiple paracrine morphogenetic cues, is mediated via an increasing number of important transcriptional regulators. Hypoxia promotes chondrocytic differentiation^–. Runx2 and Osx are globally required for skeletal ossification, while the Msx1 and Msx2 play essential roles in craniofacial bone and tooth formation. The nuclear transcriptional co-adapter β-catenin is indispensible in osteoblast differentiation, interacting with TCF/LEF and Smad transcriptional complexes. With arteriosclerotic vascular calcification, osteoprogenitors can arise from VSMC transdifferentiation, lineage osteogenic allocation of multipotent vascular mesenchymal progenitors, and from endothelilal lineage cells undergoing endothelial-mesenchymal transitioning (EMT). See text for details.

Figure 2. The essentials of osteogenic BMP signaling in arteriosclerotic calcification

Vascular expression of BMP2 and BMP4, elaborated in great part by endothelial cells, is entrained to diabetes, dyslipidemia, inflammation, oxidative stress, and shear. Nuclear R-Smads mediate transcriptional transactivation both via intrinsic Smad complex DNA binding activity and as transactivators via interactions with other factors such as Runx2. The down-stream pro-osteogenic signaling cascades initiated via heterodimer BMP receptors is held in check by a panoply of extracellular BMP binding proteins and intracellular transcriptional inhibitors (I-Smads). Key features of BMP action in osteoprogenitors includes the upregulation of paracrine Wnt signals ^, . See text for details. (Illustration Credit: Cosmocyte/Ben Smith).

Figure 3. The essentials of osteogenic Wnt signaling in arteriosclerotic calcification

Vascular expression of a large family of Wnts, elaborated by endothelial cells, mesenchymal cells, and macrophages^{, , ,} , is entrained to diabetes and oxidative stress via BMP, TNF, and Msx genomic relays. Down-stream pro-osteogenic signaling cascades initiated via heterodimeric LRP:Fzd receptors is held in check by extracellular LRP receptor antagonists (Dkks, SOST), binding proteins (sFRPs) and intracellular transcriptional inhibitors (ICAT). The osteogenic differentiation programs dependent upon BMP induction require β-catenin regulated trans-activation, achieved by the activation of canonical Wnt/LRP signaling. Not shown are the LRP-independent Fzd and ROR2 signaling complexes that can mediate other Wnt actions, and the emerging roles of connective tissue growth factor, R-spondins^–, and tissue transglutaminase -2 as canonical LRP agonists. See text for details. (Illustration Credit: Cosmocyte/Ben Smith).