Ectopic calcification of rat aortas and kidneys is reduced with n-3 fatty acid supplementation

Schlemmer, C.K.; Coetzer, H.; Claassen, Nico; Kruger, Marlena C.; Rademeyer, C.; Jaarsveld, L. van; Smuts, Cornelius M.

doi:10.1016/s0952-3278(98)90066-7

Cited by 24 publications

(9 citation statements)

References 14 publications

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“…This finding is somewhat similar to the clinical picture seen in the elderly, in whom osteoporosis is associated with calcification of the arteries and kidneys (9) . It has been reported that the increased deposition of calcium in both kidneys and aorta was reduced by FO and EPA in male Sprague‐Dawley rats (42) . A well‐controlled human study also revealed that polyunsaturated fatty acids (PUFAs) such as GLA and EPA have beneficial effects on bone density in elderly people (38) .…”

Section: Discussionsupporting

confidence: 77%

Dietary n-3 Fatty Acids Decrease Osteoclastogenesis and Loss of Bone Mass in Ovariectomized Mice

Sun

Krishnan

Zaman

et al. 2003

Journal of Bone and Mineral Research

258

219

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The mechanisms of action of dietary fish oil (FO) on osteoporosis are not fully understood. This study showed FO decreased bone loss in ovariectomized mice because of inhibition of osteoclastogenesis. This finding supports a beneficial effect of FO on the attenuation of osteoporosis.Introduction: Consumption of fish or n-3 fatty acids protects against cardiovascular and autoimmune disorders. Beneficial effects on bone mineral density have also been reported in rats and humans, but the precise mechanisms involved have not been described. Methods: Sham and ovariectomized (OVX) mice were fed diets containing either 5% corn oil (CO) or 5% fish oil (FO). Bone mineral density was analyzed by DXA. The serum lipid profile was analyzed by gas chromatography. Receptor activator of NF-B ligand (RANKL) expression and cytokine production in activated T-cells were analyzed by flow cytometry and ELISA, respectively. Osteoclasts were generated by culturing bone marrow (BM) cells with 1,25(OH) 2 D 3 . NF-B activation in BM macrophages was measured by an electrophoretic mobility shift assay. Results and Conclusion: Plasma lipid C16:1n6, C20:5n3, and C22:6n3 were significantly increased and C20:4n6 and C18:2n6 decreased in FO-fed mice. Significantly increased bone mineral density loss (20% in distal left femur and 22.6% in lumbar vertebrae) was observed in OVX mice fed CO, whereas FO-fed mice showed only 10% and no change, respectively. Bone mineral density loss was correlated with increased RANKL expression in activated CD4 ϩ T-cells from CO-fed OVX mice, but there was no change in FO-fed mice. Selected n-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) added in vitro caused a significant decrease in TRACP activity and TRACP ϩ multinuclear cell formation from BM cells compared with selected n-6 fatty acids (linoleic acid [LA] and arachidonic acid [AA]). DHA and EPA also inhibited BM macrophage NF-B activation induced by RANKL in vitro. TNF-␣, interleukin (IL)-2, and interferon (IFN)-␥ concentrations from both sham and OVX FO-fed mice were decreased in the culture medium of splenocytes, and interleukin-6 was decreased in sham-operated FO-fed mice. In conclusion, inhibition of osteoclast generation and activation may be one of the mechanisms by which dietary n-3 fatty acids reduce bone loss in OVX mice.

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Section: Discussionsupporting

confidence: 77%

Dietary n-3 Fatty Acids Decrease Osteoclastogenesis and Loss of Bone Mass in Ovariectomized Mice

Sun

Krishnan

Zaman

et al. 2003

Journal of Bone and Mineral Research

258

219

View full text Add to dashboard Cite

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“…43 Similarly, omega-3 fatty acids (fish oils), which are known to be anti-atherogenic from the basic science to the clinical level, also inhibit vascular cell calcification in vitro, by acting through p38-MAPK and peroxisome-proliferator activated receptor (PPAR)-gamma pathways, 44 and they are also effective in vivo. 45 As further evidence for a role of lipids in vascular cell calcification, the farnesyl X receptor (FXR), a nuclear hormone receptor activated by derivatives of the isoprenyl lipid, farnesol, is upregulated during osteogenic differentiation of vascular cells. 46 A synthetic FXR activator, INT-747, prevents vascular calcification in uremic, hyperlipidemic mice.…”

Section: Oxylipidsmentioning

confidence: 99%

The Roles of Lipid Oxidation Products and Receptor Activator of Nuclear Factor-κB Signaling in Atherosclerotic Calcification

Demer

Tintut

2011

Circulation Research

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This review focuses on the roles of oxylipids and receptor activator of nuclear factor-kappa B ligand (RANKL) signaling in calcific cardiovascular disease. Both intimal and valvular calcification are closely associated with atherosclerosis, leading investigators to study the role of atherogenic oxidatively modified lipids (oxylipids). Results have identified the molecular signaling through which oxylipids induce osteogenic differentiation and calcification in vascular cells. A surprising concomitant finding was that, in bona fide osteoblasts from skeletal bone, oxylipids have the opposite effect, i.e. inhibiting osteoblastic maturation. This is the basis for the lipid hypothesis of osteoporosis. Oxylipids also induce resorptive osteoclastic cells within the bone environment, raising the question of whether resorptive osteoclasts can be harnessed in the vascular context for cell-based therapy to remove artery wall mineral deposits. The challenge is that, vascular cells produce anti-osteoclastogenic factors, including the soluble decoy receptor for RANKL, possibly accounting for the paucity of resorptive cells and the dominance of mineral in atherosclerotic plaque. These factors may have therapeutic use in osteoclastogenic removal of mineral deposits from arteries.

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“…There have been some reports describing the inhibitory effects of EPA or n-3 PUFAs on ectopic calcification. N-3 PUFAs supplementation has been described to reduce ectopic calcification in vivo [14], [15]. Two recent studies show that EPA inhibits warfarin-induced arterial medial calcification in rats [16], and mineralization of calcifying vascular cells (CVC) in vitro [17].…”

Section: Introductionmentioning

confidence: 99%

Palmitic Acid Induces Osteoblastic Differentiation in Vascular Smooth Muscle Cells through ACSL3 and NF-κB, Novel Targets of Eicosapentaenoic Acid

et al. 2013

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Free fatty acids (FFAs), elevated in metabolic syndrome and diabetes, play a crucial role in the development of atherosclerotic cardiovascular disease, and eicosapentaenoic acid (EPA) counteracts many aspects of FFA-induced vascular pathology. Although vascular calcification is invariably associated with atherosclerosis, the mechanisms involved are not completely elucidated. In this study, we tested the hypothesis that EPA prevents the osteoblastic differentiation and mineralization of vascular smooth muscle cells (VSMC) induced by palmitic acid (PA), the most abundant long-chain saturated fatty acid in plasma. PA increased and EPA abolished the expression of the genes for bone-related proteins, including bone morphogenetic protein (BMP)-2, Msx2 and osteopontin in human aortic smooth muscle cells (HASMC). Among the long-chain acyl-CoA synthetase (ACSL) subfamily, ACSL3 expression was predominant in HASMC, and PA robustly increased and EPA efficiently inhibited ACSL3 expression. Importantly, PA-induced osteoblastic differentiation was mediated, at least in part, by ACSL3 activation because acyl-CoA synthetase (ACS) inhibitor or siRNA targeted to ACSL3 completely prevented the PA induction of both BMP-2 and Msx2. Conversely, adenovirus-mediated ACSL3 overexpression enhanced PA-induced BMP-2 and Msx2 expression. In addition, EPA, ACSL3 siRNA and ACS inhibitor attenuated calcium deposition and caspase activation induced by PA. Notably, PA induced activation of NF-κB, and NF-κB inhibitor prevented PA-induction of osteoblastic gene expression and calcium deposition. Immunohistochemistry revealed the prominent expression of ACSL3 in VSMC and macrophages in human non-calcifying and calcifying atherosclerotic plaques from the carotid arteries. These results identify ACSL3 and NF-κB as mediators of PA-induced osteoblastic differentiation and calcium deposition in VSMC and suggest that EPA prevents vascular calcification by inhibiting such a new molecular pathway elicited by PA.

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Ectopic calcification of rat aortas and kidneys is reduced with n-3 fatty acid supplementation

Cited by 24 publications

References 14 publications

Dietary n-3 Fatty Acids Decrease Osteoclastogenesis and Loss of Bone Mass in Ovariectomized Mice

Dietary n-3 Fatty Acids Decrease Osteoclastogenesis and Loss of Bone Mass in Ovariectomized Mice

The Roles of Lipid Oxidation Products and Receptor Activator of Nuclear Factor-κB Signaling in Atherosclerotic Calcification

Palmitic Acid Induces Osteoblastic Differentiation in Vascular Smooth Muscle Cells through ACSL3 and NF-κB, Novel Targets of Eicosapentaenoic Acid

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