Bone loss and IL17A

[Mike Bartolatz]

Copyright ©2010 Adamopoulos et al.; licensee BioMed Central Ltd.
Interleukin-17A upregulates receptor activator of NF-κB on osteoclast precursors
Iannis E Adamopoulos,1 Cheng-chi Chao,1 Richard Geissler,2 Drake Laface,1 Wendy Blumenschein,1 Yoichiro Iwakura,3 Terrill McClanahan,1 and Edward P Bowman1
1Discovery Research, Schering-Plough Biopharma (formerly DNAX Research, Inc.), 901 South California Avenue, Palo Alto, CA 94304, USA
2Schering Plough Research Institute, 144 State Route 94, Lafayette, NJ 07848, USA
3Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Corresponding author.
Iannis E Adamopoulos: iannis.adamopoulos@spcorp.com ; Cheng-chi Chao: cheng-chi@spcorp.com ; Richard Geissler: richard.geissler@spcorp.com ; Drake Laface: drake.laface@spcorp.com ; Wendy Blumenschein: wendy.blumenschein@spcorp.com ; Yoichiro Iwakura: iwakura@ims.u-tokyo.ac.jp ; Terrill McClanahan: Terri.McClanahan@spcorp.com ; Edward P Bowman: Eddie.bowman@spcorp.com
Received September 2, 2009; Revisions requested November 3, 2009; Revised January 31, 2010; Accepted February 18, 2010.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Introduction
The interaction between the immune and skeletal systems is evidenced by the bone loss observed in autoimmune diseases such as rheumatoid arthritis. In this paper we describe a new mechanism by which the immune cytokine IL-17A directly affects osteoclastogenesis.
Methods
Human CD14+ cells were isolated from healthy donors, cultured on dentine slices and coverslips and stimulated with IL-17A and/or receptor activator of NF-κB ligand (RANKL). Osteoclast differentiation was evaluated by gene expression, flow cytometry, tartrate-resistant acid phosphatase staining, fluorescence and electron microscopy. Physiologic bone remodelling was studied in wild-type (Wt) and IL-17A-/- mice using micro-computer tomography and serum RANKL/osteoprotegerin concentration. Functional osteoclastogenesis assays were performed using bone marrow macrophages isolated from IL-17A-/- and Wt mice.
Results
IL-17A upregulates the receptor activator for NF-κB receptor on human osteoclast precursors in vitro, leading to increased sensitivity to RANKL signalling, osteoclast differentiation and bone loss. IL-17A-/- mice have physiological bone homeostasis indistinguishable from Wt mice, and bone marrow macrophages isolated from these mice develop fully functional normal osteoclasts.
Conclusions
Collectively our data demonstrate anti-IL-17A treatment as a selective therapeutic target for bone loss associated with autoimmune diseases.

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