HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Quinn, J. M. W. Articles by Gillespie, M. T. Search for Related Content PubMed PubMed Citation Articles by Quinn, J. M. W. Articles by Gillespie, M. T.

IL-23 Inhibits Osteoclastogenesis Indirectly through Lymphocytes and Is Required for the Maintenance of Bone Mass in Mice¹

Julian M. W. Quinn^2,*,, Natalie A. Sims^*,, Hasnawati Saleh^*,, Danijela Mirosa^*, Keith Thompson^*,, Stelios Bouralexis^*, Emma C. Walker^*, T. John Martin^*, and Matthew T. Gillespie^*,

^* St Vincent’s Institute, Fitzroy, Victoria, Australia; Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, Australia; and Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom

IL-23 stimulates the differentiation and function of the Th17 subset of CD4⁺ T cells and plays a critical role in chronic inflammation. The IL-23 receptor-encoding gene is also an inflammatory disease susceptibility gene. IL-23 shares a common subunit with IL-12, a T cell-dependent osteoclast formation inhibitor, and we found that IL-23 also dose-dependently inhibited osteoclastogenesis in a CD4⁺ T lymphocyte-dependent manner. When sufficiently enriched, T cells also mediated IL-23 inhibition. Like IL-12, IL-23 acted synergistically with IL-18 to block osteoclastogenesis but, unlike IL-12, IL-23 action depended on T cell GM-CSF production. IL-23 did not mediate IL-12 action although IL-12 induced its expression. Male mice lacking IL-23 (IL-23p19^–/–) had 30% lower bone mineral density and tibial trabecular bone mass (bone volume (BV)/total volume (TV)) than wild-type littermates at 12 wk and 40% lower BV/TV at 26 wk of age; male heterozygotes also had lower bone mass. Female IL-23p19^–/– mice also had reduced BV/TV. IL-23p19^–/– mice had no detectable osteoclast defect in trabecular bone but IL-23p19^–/– had thinner growth plate hypertrophic and primary spongiosa zones (and, in females, less cartilage remnants) compared with wild type. This suggests increased osteoclast action at and below the growth plate, leading to reduced amounts of mature trabecular bone. Thus, IL-23 inhibits osteoclast formation indirectly via T cells in vitro. Under nonpathological conditions (unlike inflammatory conditions), IL-23 favors higher bone mass in long bones by limiting resorption of immature bone forming below the growth plate.

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 supported by Program Grant 345401 from the National Health and Medical Research Council of Australia.

² Address correspondence and reprint requests to Dr. Julian Quinn, St. Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia. E-mail address: jquinn{at}svi.edu.au

³ Abbreviations used in this paper: RANKL, receptor activator of NF-B ligand; 1,25(OH)₂ D₃, 1,25-dihydroxyvitamin D₃; BMM, bone marrow macrophage; pQCT, peripheral quantitative computer-aided tomography; Ct, cortical; Tb, trabecular; WT, wild type; BMD, bone mineral density; TRAP, tartrate-resistant acid phosphatase; MNC, multinucleated cell; BV, bone volume; TV, Tb volume.