Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in
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              ldlr
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            Mice

Morony, Sean; Tintut, Yin; Zhang, Zina; Cattley, Russell C.; Van, Gwyneth; Dwyer, Denise; Stolina, Marina; Kostenuik, Paul J.; Demer, Linda L.

doi:10.1161/circulationaha.107.707380

Cited by 240 publications

(210 citation statements)

References 49 publications

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“…Calcification commonly complicates longstanding atherosclerosis, and the absence of OPG in OPG/apoE double knockout mice accelerates calcific atherosclerosis that develops in apoE−/− mice (75). These findings suggest that OPG could also limit calcification of atherosclerotic plaques (76). However, whether OPG or RANKL play important roles in cardiovascular disease remains to be determined and is controversial (77).…”

Section: Opgmentioning

confidence: 99%

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Boyce

Xing

2008

Archives of Biochemistry and Biophysics

1,479

1,058

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The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-κB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/ OPG system in bone modeling and remodeling. KeywordsBone resorption; osteoclasts; RANKL; RANK; OPG Normal bone modelingWith the exception of the bones of the calvaria, all bones in the mammalian skeleton are preformed in cartilage moulds from mesenchymal progenitors, which under appropriate stimuli also have the potential to differentiate into a variety of tissue types, including fibrous tissue, fat and muscle. Chondrocytes proliferate near the ends of the cartilage moulds to drive their longitudinal growth, while others in the centers of undergo hypertrophic differentiation. The hypertrophic chondrocytes at the periphery of the centers of these moulds are invaded by blood vessels and undergo apoptosis. Some of this hypertrophic cartilage survives as thin islands of cartilage in the centers of ossification in growing bones. Osteoblasts, which differentiate from progenitors in a collar of connective tissue around the middle of the bones where vascular invasion takes place, follow the endothelial cells and lay down bone matrix on the surfaces of these islands of cartilage to form bone struts or trabeculae (1). Osteoclast precursors (OCPs), derived from progenitors in the spleen and liver are attracted from blood in the invading blood vessels close to newly formed bone trabeculae. These osteoclast precursors fuse with one

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Section: Opgmentioning

confidence: 99%

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Boyce

Xing

2008

Archives of Biochemistry and Biophysics

1,479

1,058

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“…In this study, CKD together with high-fat diet also increased both intimal and medial calcification. In another study of LDR Ϫ/Ϫ mice that were fed an atherogenic diet, treatment with recombinant osteoprotegerin reduced the calcification area and the expression of osteocalcin, a marker of mineralization, without affecting size or number of aortic atherosclerotic lesions (54). In an animal model of type 2 diabetes, TNF-␣ was shown to induce the MSX-Wnt osteogenic program that regulates arterial calcification (32).…”

Section: To What Extent Can We Use Data From Animal Studies To Solve mentioning

confidence: 99%

Media Calcification and Intima Calcification Are Distinct Entities in Chronic Kidney Disease

Amann¹

2008

Clinical Journal of the American Society of Nephrology

336

243

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Calcification of the vascular tree is common in physiologic and pathologic conditions, i.e., aging, diabetes, dyslipidemia, genetic diseases, and diseases with disturbances of calcium metabolism. In chronic kidney disease, vascular calcification is even more common, develops early, and contributes to the markedly increased cardiovascular risk in this particular population. Pathomorphologically, atherosclerosis (i.e., plaque-forming degenerative changes of the aorta and of large elastic arteries) and arteriosclerosis (i.e., concentric media thickening of muscular arteries) can be distinguished. Increasing knowledge about calcification together with improved imaging techniques provided evidence that also vascular calcification has to be divided into two distinct entities according to the specific sites of calcification within the vascular wall: Patchy calcification of the intima in the vicinity of lipid or cholesterol deposits as present in plaque calcification and calcification of the media in the absence of such lipid or cholesterol deposits, known as Mö nckeberg-type atherosclerosis. The two types of calcification may vary according to the type of vessel (large elastic versus smaller muscular type artery) and proximal versus distal sites of the arterial tree. Furthermore, clinical studies showed that it is not purely academic to distinguish between intimal and medial calcification but rather relevant for the clinical presentation, treatment, and prognosis because each type leads to different clinical consequences. In vivo studies in animal models provided evidence in favor of common pathomechanisms between vascular calcification and atherosclerosis; however, there is other, strong experimental and clinical evidence that pleads for the continued distinction between intimal and medial calcification.

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“…Real-time reverse-transcriptase polymerase chain reaction (RT-qPCR) was performed using the One-Step qRT-PCR SuperMix Kit (BioChain Institute, Inc., Hayward, CA, USA) and Mx3005P Real-Time PCR System (Agilent Technologies, Inc., Wilmington, DE, USA), as described previously. (27)(28)(29) Statistical analysis HFD effects on gene expression and bone parameters were compared in chow versus HFD groups by Student's t test. Comparisons across more than two groups were performed with two-way ANOVA, followed by the Fisher's PLSD test using…”

Section: Real-time Rt-qpcrmentioning

confidence: 99%

Hyperlipidemia induces resistance to PTH bone anabolism in mice via oxidized lipids

Sage

Atti

et al. 2010

Journal of Bone and Mineral Research

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In hyperlipidemia, oxidized lipids accumulate in vascular tissues and trigger atherosclerosis. Such lipids also deposit in bone tissues, where they may promote osteoporosis. We found previously that oxidized lipids attenuate osteogenesis and that parathyroid hormone (PTH) bone anabolism is blunted in hyperlipidemic mice, suggesting that osteoporotic patients with hyperlipidemia may develop resistance to PTH therapy. To determine if oxidized lipids account for this PTH resistance, we blocked lipid oxidation products in hyperlipidemic mice with an ApoA-I mimetic peptide, D-4F, and the bone anabolic response to PTH treatment was assessed. Skeletally immature Ldlr À/À mice were placed on a high-fat diet and treated with D-4F peptide and/or with intermittent PTH(1-34) injections. As expected, D-4F attenuated serum lipid oxidation products and tissue lipid deposition induced by the diet. Importantly, D-4F treatment attenuated the adverse effects of dietary hyperlipidemia on PTH anabolism by restoring micro-computed tomographic parameters of bone quality-cortical mineral content, area, and thickness. D-4F significantly reduced serum markers of bone resorption but not bone formation. PTH and D-4F, together but not separately, also promoted bone anabolism in an alternative model of hyperlipidemia, Apoe À/À mice. In normolipemic mice, D-4F cotreatment did not further enhance the anabolic effects of PTH, indicating that the mechanism is through its effects on lipids. These findings suggest that oxidized lipids mediate hyperlipidemia-induced PTH resistance in bone through modulation of bone resorption. ß

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Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr ^(−/−) Mice

Cited by 240 publications

References 49 publications

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Media Calcification and Intima Calcification Are Distinct Entities in Chronic Kidney Disease

Hyperlipidemia induces resistance to PTH bone anabolism in mice via oxidized lipids

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Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr (−/−) Mice

Cited by 240 publications

References 49 publications

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Media Calcification and Intima Calcification Are Distinct Entities in Chronic Kidney Disease

Hyperlipidemia induces resistance to PTH bone anabolism in mice via oxidized lipids

Contact Info

Product

Resources

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Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr ^(−/−) Mice