BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells

Li, Xianwu; Yang, Hongyan; Giachelli, Cecilia M.

doi:10.1016/j.atherosclerosis.2007.11.031

Cited by 242 publications

(225 citation statements)

References 35 publications

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“…The low basal levels may have been the basis for the absence of a highphosphorus media effect to reduce their expression, as shown by other investigators. 11,36 Our data demonstrating inhibition of a BMP-2/4 directed program by another closely related BMP that is generally but not always 37 complementary in osteoblast function, BMP-7, is not surprising. This is exactly what occurs in several biologic situations, including kidney development, in which BMP-2 inhibits BMP-7-stimulated branching morphogenesis 38 -also, in collecting duct function, in which BMP-2 inhibited proliferation and induced apoptosis, whereas low-dosage BMP-7 stimulated proliferation.…”

Section: Vc In the Ldlrmentioning

confidence: 90%

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

Mathew¹,

Tustison²,

Sugatani³

et al. 2008

Journal of the American Society of Nephrology

208

169

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Hyperphosphatemia and vascular calcification have emerged as cardiovascular risk factors among those with chronic kidney disease. This study examined the mechanism by which phosphorous stimulates vascular calcification, as well as how controlling hyperphosphatemia affects established calcification. In primary cultures of vascular smooth muscle cells derived from atherosclerotic human aortas, activation of osteoblastic events, including increased expression of bone morphogenetic protein 2 (BMP-2) and the transcription factor RUNX2, which normally play roles in skeletal morphogenesis, was observed. These changes, however, did not lead to matrix mineralization until the phosphorus concentration of the media was increased; phosphorus stimulated expression of osterix, a second critical osteoblast transcription factor. Knockdown of osterix with small interference RNA (siRNA) or antagonism of BMP-2 with noggin prevented matrix mineralization in vitro. Similarly, vascular BMP-2 and RUNX2 were upregulated in atherosclerotic mice, but significant mineralization occurred only after the induction of renal dysfunction, which led to hyperphosphatemia and increased aortic expression of osterix. Administration of oral phosphate binders or intraperitoneal BMP-7 decreased expression of osterix and aortic mineralization. It is concluded that, in chronic kidney disease, hyperphosphatemia stimulates an osteoblastic transcriptional program in the vasculature, which is mediated by osterix activation in cells of the vascular tunica media and neointima. Chronic kidney disease (CKD) is a fatal illness, and cardiovascular complications are the major causes of morbidity and mortality. 1,2 The causes of the excess cardiovascular mortality associated with CKD are unknown, because the role of the standard risk factors associated with cardiovascular mortality do not account for the increased risk in CKD. 2 There is strong epidemiologic evidence that serum phosphorus is an independent risk factor for cardiovascular events and mortality in CKD. 3,4 The serum phosphorus has been linked to another cardiovascular risk factor, vascular calcification (VC), 3,5,6 an important cause of vascular stiffness in CKD leading to increased pulse wave velocity, increased cardiac work, left ventricular hypertrophy, and decreased coronary artery blood flow. 6 -8 Phosphorus has been further implicated as a cause of VC through studies in vitro that have demonstrated that it induces phenotypic changes in vascular smooth muscle cells (VSMC) by increasing gene transcription of proteins involved in osteoblast function-bone formation 9 and stimulating matrix mineralization. 10 -12 In the uremic calcifying environment, expression of the contractile proteins of VSMC, such as ␣-smooth muscle actin, SM22,

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Section: Vc In the Ldlrmentioning

confidence: 90%

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

Mathew¹,

Tustison²,

Sugatani³

et al. 2008

Journal of the American Society of Nephrology

208

169

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“…In addition, lovastatin has been shown to stimulate the expression of BMP-2 in VSMCs (43) and osteoblasts (44). BMP-2 is a causative factor in vascular calcification (45) and has been shown to induce the osteogenic differentiation of VSMCs (46). Furthermore, HMGCoA reductase inhibitors have been shown to induce apoptosis in pericytes (47), which also appear to contribute to vascular calcification (27), and enhanced apoptosis is associated with enhanced vascular calcification both in vitro and in vivo (48 -50).…”

Section: Discussionmentioning

confidence: 99%

Apposite Insulin-like Growth Factor (IGF) Receptor Glycosylation Is Critical to the Maintenance of Vascular Smooth Muscle Phenotype in the Presence of Factors Promoting Osteogenic Differentiation and Mineralization

Siddals

Allen

Sinha

et al. 2011

Journal of Biological Chemistry

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The importance of vascular calcification in the development and progression of cardiovascular disease is well established (1, 2), and it is known to be a predictor of future cardiovascular events (3). Vascular calcification is an active cell-mediated process, involving the osteoblastic conversion of vascular smooth muscle cells (VSMCs), 2 calcifying vascular cells, pericytes, and adventitial myofibroblasts (4 -9). In vivo, vascular calcification has been shown to result from an endochondral ossification-like process, resulting in the formation of bone as well as both marrow and cartilage (10 -12).A previous study from Demer and co-workers (13) has shown that insulin-like growth factor-I (IGF-I) prevents the osteoblastic conversion of calcifying vascular cells. The role of IGF-I in the terminal differentiation of multiple cell types is well known (14 -16), but its role in phenotype maintenance is less well understood. We have previously shown that IGF signaling can be attenuated in 3T3-L1 cells using HMG-CoA reductase inhibitors through their effects on IGF receptor (IGFR) glycosylation and Ras prenylation (17). Therefore, by removing this protective pathway, we hypothesized that HMG-CoA reductase inhibitors would also render vascular cells more vulnerable to osteogenic differentiation and subsequent mineralization. This hypothesis is consistent with a recent study showing that atorvastatin promotes osteogenic differentiation and calcium deposition by VSMCs (18) and osteoblast cell lines (19,20) in vitro. However, there are also reports that HMG-CoA reductase inhibitors inhibit the osteoblastic conversion of human VSMCs (21, 22) and TGF␤-induced calcific nodule formation by valvular interstitial cells (23,24). The reason for these discrepancies is not clear but may reflect differences in the factors used to stimulate differentiation in these studies.Therefore, the purpose of this study was (i) to determine the importance of IGF signaling in promoting the proliferation and preventing the osteogenic differentiation of VSMCs, (ii) to determine whether HMG-CoA reductase inhibitors modulate the inhibitory effect of IGF-I on the osteogenic differentiation of VSMCs, and (iii) to elucidate the mechanism by which this modulation occurs. Our data show that cerivastatin, through alterations in IGFR glycosylation, attenuates the protective effect of IGF-I on VSMCs by preventing IGFR processing and cell-surface localization.

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“…CAS is characterized by valve thickening and stenosis of the orifice area triggered by an overactive inflammatory process involving expression of cytokines, including tumor necrosis factor-a (TNF-a) [2], transforming growth factor-beta 1 [3], and interleukin-1 beta (IL-1beta) [4]. These cytokines contribute to extracellular matrix formation, remodeling, and ectopic calcification, which are accelerated in the presence of high inorganic phosphate (2.2-3.2 mM) [5][6][7]. Although we recently demonstrated that TNF-a-induces aortic valve calcification in patients with CAS [8], the cellular origin of ectopic calcification remains unclear.…”

Section: Introductionmentioning

confidence: 99%

CD34-negative mesenchymal stem-like cells may act as the cellular origin of human aortic valve calcification

Nomura

Seya

et al. 2013

Biochemical and Biophysical Research Communications

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Although various osteogenic inducers contribute to the calcification of human aortic valve interstitial cells, the cellular origin of calcification remains unclear. We immunohistochemically investigated the cellular origin of valve calcification using enzymatically isolated cells from both calcified and non-calcified human aortic valve specimens. CD73-, 90-, and 105-positive and CD45-negative mesenchymal stem-like cells (MSLCs) were isolated from both types of valve specimens using fluorescence-activated cell sorting. MSLCs were further sorted into CD34-negative and -positive cells. Compared with CD34-positive cells, CD34-negative MSLCs were significantly more sensitive to high inorganic phosphate (3.2 mM), calcifying easily in response. Furthermore, immunohistochemical staining showed that significantly higher numbers (～7-9-fold) of CD34-negative compared with CD34-positive MSLCs were localized in calcified aortic valve specimens obtained from calcified aortic stenosis patients. These results suggest that CD34-negative MSLCs are responsible for calcification of the aortic valve.

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BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells

Cited by 242 publications

References 35 publications

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

Apposite Insulin-like Growth Factor (IGF) Receptor Glycosylation Is Critical to the Maintenance of Vascular Smooth Muscle Phenotype in the Presence of Factors Promoting Osteogenic Differentiation and Mineralization

CD34-negative mesenchymal stem-like cells may act as the cellular origin of human aortic valve calcification

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