Homocysteine alters the osteoprotegerin/RANKL system in the osteoblast to promote bone loss: pivotal role of the redox regulator forkhead O1

Vijayan, Viji and Khandelwal, Mayuri and Manglani, Kapil and Singh, Rajiv Ranjan and Gupta, Sarika and Surolia, Avadhesha (2013) Homocysteine alters the osteoprotegerin/RANKL system in the osteoblast to promote bone loss: pivotal role of the redox regulator forkhead O1. In: FREE RADICAL BIOLOGY AND MEDICINE, 61 . pp. 72-84.

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Abstract

In this study we determined the molecular mechanisms of how homocysteine differentially affects receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG) synthesis in the bone. The results showed that oxidative stress induced by homocysteine deranges insulin-sensitive FOXO1 and MAP kinase signaling cascades to decrease OPG and increase RANKL synthesis in osteoblast cultures. We observed that downregulation of insulin/FOXO1 and p38 MAP kinase signaling mechanisms due to phosphorylation of protein phosphatase 2 A (PP2A) was the key event that inhibited OPG synthesis in homocysteine-treated osteoblast cultures. siRNA knockdown experiments confirmed that FOXO1 is integral to OPG and p38 synthesis. Conversely homocysteine increased RANKL synthesis in osteoblasts through c-Jun/JNK MAP kinase signaling mechanisms independent of FOXO1. In the rat bone milieu, high-methionine diet-induced hyperhomocysteinemia lowered FOXO1 and OPG expression and increased synthesis of proresorptive and inflammatory cytokines such as RANKL, M-CSF, IL-1 alpha, IL-1 beta, G-CSF, GM-CSF, MIP-1 alpha, IFN-gamma, IL-17, and TNF-alpha. Such pathophysiological conditions were exacerbated by ovariectomy. Lowering the serum homocysteine level by a simultaneous supplementation with N-acetylcysteine improved OPG and FOXO1 expression and partially antagonized RANKL and proresorptive cytokine synthesis in the bone milieu. These results emphasize that hyperhomocysteinemia alters the redox regulatory mechanism in the osteoblast by activating PP2A and deranging FOXO1 and MAPK signaling cascades, eventually shifting the OPG:RANKL ratio toward increased osteoclast activity and decreased bone quality (C) 2013 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Publication:	FREE RADICAL BIOLOGY AND MEDICINE
Publisher:	ELSEVIER SCIENCE INC
Additional Information:	Copyright of this article is belongs to ELSEVIER
Keywords:	Osteoprotegerin; Receptor activator of nuclear; factor-kappa B ligand; Forkhead box; p38; Protein phosphatase 2 A; c-Jun MAP kinase; Free radicals
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	03 Sep 2013 08:39
Last Modified:	03 Sep 2013 08:39
URI:	http://eprints.iisc.ac.in/id/eprint/47029

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