TGF-beta 1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify.

Abstract

Previous studies in our laboratory demonstrated messenger RNA for bone morphogenetic protein-2a in human calcified plaque, suggesting that arterial calcification is a regulated process, similar to osteogenesis. To further test this hypothesis, we have isolated and cloned a subpopulation of cells from bovine aortic media that show osteoblastic potential. These novel cells are primarily distinguished from smooth muscle cells by expression of a surface marker preliminarily identified as a modified form of the ganglioside sialyl-lactosylceramide (GM3). Osteoblastic potential was indicated by high levels of alkaline phosphatase and collagen I, expression of osteopontin and osteonectin (SPARC), and production of bone-specific osteocalcin and hydroxyapatite. Cultures of these cells were stimulated to form increased numbers of calcium-mineral-producing nodules by the oxysterol 25-hydroxycholesterol as well as by transforming growth factor-?1, both known to be present in atherosclerotic lesions. The stimulation of calcifying vascular cells in the artery wall by these two factors suggests a possible mechanism for the colocalization of calcification with atherosclerosis in vivo. (J. Clin. Invest. 1994. 93:2106-2113

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE −/− Mice

“…14 SMCs can be converted to osteogenic cells in vitro suggesting that they may play a role in vascular calcification in vivo. 41,42 In the current study we found that the increase in medial calcification preceded the increase in lesion area and lesion calcification. Thus, it is conceivable that the absence of OPG leads to an increase in smooth muscle cell derived osteogenic cells in the media that are then recruited into the developing lesion.…”

“…43 Furthermore, proinflammatory cytokines such as tumor necrosis factor-␣ increase the conversion of SMCs to an osteogenic phenotype in vitro. 42,44 Thus there is the possibility that calcification itself increases plaque burden by further activating pro- 26 we have observed a significant increase in circulating alkaline phosphatase in these mice (data not shown). Recently, osteoporosis has been identified as an independent risk factor for mortality in renal patients 45 who are also at increased risk for cardiovascular disease.…”

Acetylated Low-Density Lipoprotein Stimulates Human Vascular Smooth Muscle Cell Calcification by Promoting Osteoblastic Differentiation and Inhibiting Phagocytosis

“…23,24 We have extended these studies in human VSMCs and investigated the expression of several bone marker genes as well as the role of lipoproteins in apoptosis and apoptotic body clearance. This study demonstrates, for the first time, that an osteogenic phenotype of VSMCs exists in atherosclerotic lesions in association with sites of lipid accumulation and calcification.…”

Eosinophils: a new player in coronary atherosclerotic disease

“…21 Interestingly, of these factors, transforming growth factor-beta has been reported to enhance in vitro calcification of vascular cells. 22 Finally, eosinophils synthesize and release bioactive mediators, such as leukotriene C4, a potent stimulant of vasoactivity and smooth muscle contraction, and they can induce the release of a number of vasoactive substances, including histamine, prostaglandin D2 and leukotrienes C4 and D4, from mast cells and basophils. 19 Interestingly, eosinophil activation can be monitored by using serum biomarkers, among which ECP, a zinc-containing, highly cationic protein that is stored in peroxidasepositive and negative eosinophil granules, stands out.…”