Lipoproteins transport many vitamins and hormones that have been shown to be necessary for bone formation. However, the metabolism of LDL and HDL 3 by bone-forming osteoblastic cells remains unknown. Here we report that osteoblastic cells express scavenger receptors of class B that are implicated in the uptake of cholesterol and estradiol from LDL and HDL 3 . Introduction:The bone tissue is continuously remodeled, and its integrity requires a balance between osteoclastic bone resorption and osteoblastic bone formation. Recent studies have reported the importance of triglyceride-rich lipoproteins for the delivery of lipophilic vitamins necessary for normal bone metabolism. However, the ability of osteoblastic cells to process low-and high-density lipoproteins (LDL and HDL 3 ) and the receptors involved remain unknown. Materials and Methods: Binding, competition, degradation, and selective uptake assays with LDL and HDL 3 radiolabeled in their protein and lipid moieties or with [
Advanced-glycation end products (AGEs) were recently implicated in vascular calcification, through a process mediated by RAGE (receptor for AGEs). Although a correlation between AGEs levels and vascular calcification was established, there is no evidence that reducing in vivo AGEs deposition or inhibiting AGEs-RAGE signaling pathways can decrease medial calcification. We evaluated the impact of inhibiting AGEs formation by pyridoxamine or elimination of AGEs by alagebrium on diabetic medial calcification. We also evaluated if the inhibition of AGEs-RAGE signaling pathways can prevent calcification. Rats were fed a high fat diet during 2 months before receiving a low dose of streptozotocin. Then, calcification was induced with warfarin. Pyridoxamine was administered at the beginning of warfarin treatment while alagebrium was administered 3 weeks after the beginning of warfarin treatment. Results demonstrate that AGEs inhibitors prevent the time-dependent accumulation of AGEs in femoral arteries of diabetic rats. This effect was accompanied by a reduced diabetes-accelerated calcification. Ex vivo experiments showed that N-methylpyridinium, an agonist of RAGE, induced calcification of diabetic femoral arteries, a process inhibited by antioxidants and different inhibitors of signaling pathways associated to RAGE activation. The physiological importance of oxidative stress was demonstrated by the reduction of femoral artery calcification in diabetic rats treated with apocynin, an inhibitor of reactive oxygen species production. We demonstrated that AGE inhibitors prevent or limit medial calcification. We also showed that diabetes-accelerated calcification is prevented by antioxidants. Thus, inhibiting the association of AGE-RAGE or the downstream signaling reduced medial calcification in diabetes.
Objective-The cluster of differentiation-36 (CD36) is a multifunctional protein which is recognized for its in vitro ability to take up oxidized low-density lipoproteins (oxLDL) in macrophages and is therefore considered atherogenic. It also binds LDL. Our objective was to define the physiological role of CD36 in both native LDL and oxLDL metabolism in mice. Methods and Results-Clearance studies of labeled LDL and oxLDL were conducted in wild-type, CD36 knockout (KO), scavenger receptor class B, type I (SR-BI) KO, and SR-BI/CD36 double KO mice. We found that CD36 impedes the disappearance of native LDL and favors that of oxLDL. This was confirmed by association and degradation assays with primary cultures of hepatic cells from wild-type and CD36 KO mice. In addition, our in vivo work indicates that neither SR-BI nor CD36 plays a significant role in cholesteryl esters (CE) selective uptake (SU) from oxLDL, whereas CD36, in absence of SR-BI, can selectively take CE from LDL. Conclusion-Our investigation showed for the first time that CD36 plays a significant role in oxLDL uptake in vivo in the mouse. As CD36 also retards LDL clearance, its atherogenic character may also relate to its negative effect on LDL catabolism. t is well established that high levels of plasma cholesterol associated with LDL increase the risk of developing atherosclerosis. The level of LDL in blood circulation is related to the synthesis rate of their precursors and their uptake by the liver. 1 A large part occurs through LDLreceptors (LDLr) which take up the entire LDL particles and lead to their complete degradation, a mechanism referred to as the holoparticle pathway. LDL can also selectively transfer their CE without concomitant degradation of their apolipoproteins, a process termed selective uptake (SU).SR-BI is a cell surface receptor recognized for its ability to selectively take up CE from high-density lipoproteins (HDL) 2 and LDL. 3 Our in vivo studies 4 showed that ablation of SR-BI expression in mice leads to the complete loss of LDL-CE SU early after injection. However, after an hour, an acceleration of CE disappearance was obvious in SR-BI KO mice, indicating that a SR-BI-independent pathway can rescue SR-BI deficiency. A potential candidate for the SR-BIindependent pathway is CD36, another class B scavenger receptor. This is supported by studies showing that COS cells overexpressing either SR-BI or CD36 are equipotent toward LDL-CE uptake. 5 However the physiological importance of CD36 in LDL-CE SU remains to be established in vivo. See accompanying article on page 1209LDL can undergo oxidative modification, and these are detectable in circulation. Many studies have used standard conditions generating fully oxidized LDL (oxLDL), which we refer simply as to oxLDL. Although oxLDL cannot interact with LDLr, it is known that injected oxLDL disappear faster than native LDL in rodents and that this uptake involves the liver. 6 In vivo studies by Ling et al 7 showed that the scavenger receptor class A type I/II (SR-A) is not impli...
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