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* Departments of Metabolic Disorders,
Pathology,
Laboratory Animal Resources, and
Inflammation Therupeutic Area Development, Amgen Inc., Thousand Oaks, CA 91320; and
¶ GEMpath Inc., Cedar City, UT 84720
Receptor activator of NF-
B ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. The effects of RANKL are inhibited by a soluble decoy receptor called osteoprotegerin (OPG). Total ablation of RANKL in knockout mice leads to high bone mass, lymph node agenesis, and altered lymphocyte differentiation. In contrast, RANKL inhibition via OPG suppresses bone resorption but not inflammation in animal models of inflammatory bone loss. This suggests that the immune phenotype of RANKL knockout mice is related to total RANKL ablation. We hypothesized that prenatal RANKL inhibition via OPG overexpression would suppress bone resorption without influencing lymph node formation or subsequent immune responses. Transgenic rats were created, wherein soluble OPG was overexpressed by 100-fold vs wild type (WT) controls, by gestational day 11 (i.e., before lymph node formation). The structure of lymph nodes, spleen, and thymus of OPG-transgenic (OPG-Tg) animals were comparable to those of age-matched WT rats at gestational day 19 and in adulthood. The OPG-Tg neonates had elevated bone mass, confirming the prenatal inhibition of RANKL. Adult OPG-Tg rats and OPG-Tg mice exhibited no significant functional alterations relative to WT controls when subjected to immune challenges to test for altered innate and humoral responses (e.g., contact hypersensitivity to oxazolone, IgM response to Pneumovax, IgG response to keyhole limpet hemocyanin, or cytokine response to LPS). In summary, prenatal RANKL inhibition did not impair lymph node development, nor did continuous life-long RANKL inhibition cause obvious changes in innate or humoral immune responses in mice or rats.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was support by Amgen Inc.
2 Address correspondence and reprint requests Dr. Marina Stolina, Amgen, One Amgen Center Drive, M/S 15-2-A, Thousand Oaks, CA 91320. E-mail address: mstolina{at}amgen.com
3 Abbreviations used in this paper: RANKL, receptor activator of NF-B ligand; RANK, receptor activator of NF-B; OPG, osteoprotegerin; DTH, delayed contact hypersensitivity; Tg, transgenic; WT, wild type; GD, gestational day; ApoE, apolipoprotein E; TRAP-5B, tartrate-resistant alkaline phosphatase 5B; BMD, bone mineral density; KLH, keyhole limpet hemocyanin; DEX, dexamethasone; DC, dendritic cell.
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