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Selective inhibition of mesenchymal and hematopoietic RANKL

Abstract
Receptor activator of NF-?B ligand (RANKL) is not only an essential cytokine for osteoclast differentiation, activation, and survival, but may also be involved in the pathogenesis of acute myocardial infarction (MI) and heart failure. On the basis of the fundamental role of the RANKL/osteoprotegerin (OPG) system in bone resorption, human monoclonal antibodies against human RANKL (hRANKL) such as denosumab and AMG161, the IgG1 version of denosumab, have been developed. Furthermore, hRANKL knock-in (KI) mice were recently generated which carry the human instead of the murine exon 5 in their RANKL gene. This chimeric RANKL protein is capable of inducing bone resorption in mice, while being fully inhibited by denosumab or AMG161. Furthermore, still unpublished studies in my lab provided compelling evidence that only hematopoietic and endothelial, but not stromal precursors, engraft in host bone marrow after transplantation with unfractionated bone marrow. The current proposal is based on the idea that, together with an anti-hRANKL antibody such as AMG161, hRANKL-KI mice could be used as a powerful tool to separate between the pathophysiological role of RANKL derived from mesenchymal and hematopoietic/endothelial sources. To reach this goal, we propose to lethally irradiate wild-type and hRANKL-KI mice, and to transplant them with bone marrow from hRANKL-KI and wild-type donors, respectively. In irradiated wild-type mice reconstituted with bone marrow from homozygous hRANKL-KI donors, all hematopoietic and some endothelial cells produce chimeric, humanized RANKL, while all mesenchymal cells produce murine RANKL. Thus, because AMG161 blocks human but not murine RANKL, AMG161 will block only chimeric RANKL derived from hematopoietic/endothelial sources in this model. Vice versa, when homozygous hRANKL-KI mice are reconstituted with bone marrow from wild-type mice, only humanized RANKL derived from mesenchymal sources will be blocked. Together with hRANKL-KI mice as a control for the effects of total RANKL inhibition, such a system could provide unprecedented insight into the pathophysiology of diseases in which RANKL signaling plays a role. Although this model could be exploited in a very broad fashion, we plan to focus on osteoimmunology and myocardial infarction in the current proposal. The current proposal aims to answer the following questions: 1) What is the relative contribution of RANKL derived from mesenchymal or immune/endothelial cells in the pathophysiology of sex steroid deficiency-induced bone loss? 2) Does total RANKL inhibition or selective inhibition of hematopoietic/endothelial and mesenchymal cell-derived RANKL have a beneficial effect on the healing of myocardial lesions? If successful, this proposal will significantly advance our knowledge about the pathophysiological role of hematopoietic/endothelial and mesenchymal cell-derived RANKL in osteoporosis and myocardial infarction. Osteoporosis and myocardial infarction are leading causes of disability and death in modern societies with high percentages of elderly. Thus, the proposed work may have important implications for our health care systems.
Statistik Austria science classification
301114         Cell biology
302014         Endocrinology
302032         Cardiology
403026         Veterinary physiology
Lemma
Selective RANKL inhibition
Project leader
Erben Reinhold
Duration
01.12.09-31.03.14
Programme
FWF Einzelprojekte
Type of Research
Basic research
Vetmed Research Units
Institute of Physiology, Pathohysiology and Biophysics, Unit of Physiology, Pathophysiology, and Experimental Endocrinology
Funded by
FWF - Fonds zur Förderung der wissenschaftlichen Forschung, Wien, Austria

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4 Publications

Slavic, S; Andrukhova, O; Ford, K; Handschuh, S; Latic, N; Reichart, U; Sasgary, S; Bergow, C; Hofbauer, LC; Kostenuik, PJ; Erben, RG (2018): Selective inhibition of receptor activator of NF-κB ligand (RANKL) in hematopoietic cells improves outcome after experimental myocardial infarction. J Mol Med (Berl) 96(6): 559-573.
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Streicher, C; Heyny, A; Andrukhova, O; Haigl, B; Slavic, S; Schüler, C; Kollmann, K; Kantner, I; Sexl, V; Kleiter, M; Hofbauer, LC; Kostenuik, PJ; Erben, RG (2017): Estrogen Regulates Bone Turnover by Targeting RANKL Expression in Bone Lining Cells. Sci Rep. 2017; 7(1):6460
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Erben, RG (2015): Hypothesis: Coupling between Resorption and Formation in Cancellous bone Remodeling is a Mechanically Controlled Event. Front Endocrinol (Lausanne). 2015; 6:82
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Odörfer, KI; Egerbacher, M; Unger, NJ; Weber, K; Jamnig, A; Lepperdinger, G; Kleiter, M; Sandgren, EP; Erben, RG (2011): Hematopoietic bone marrow cells participate in endothelial, but not epithelial or mesenchymal cell renewal in adult rats. J Cell Mol Med. 2011; 15(10):2232-2244
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