CTLA-4Ig-Induced T Cell Anergy Promotes Wnt-10b Production and Bone Formation in a Mouse Model

• Type of Material: Article
• Authors: Susanne Roser-Page, Atlanta Department of Veterans Affairs Medical Center; Tatyana Vikulina, Emory University; Majd Zayzafoon, University of Alabama Birmingham; M. Neale Weitzmann, Emory University
• Language: English
• Date: 2014-04-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2014 by the American College of Rheumatology.
• Final Published Version (URL): http://dx.doi.org/10.1002/art.38319
• Title of Journal or Parent Work: Arthritis and Rheumatology
• ISSN: 2326-5191
• Volume: 66
• Issue: 4
• Start Page: 990
• End Page: 999
• Grant/Funding Information: This work was supported by a grant from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (5I01BX000105).; Histomorphometry services were performed by the University of Alabama at Birmingham, Center for Metabolic Bone Disease-Histomorphometry and Molecular Analysis Core Laboratory, supported by NIAMS (P30AR46031).; MNW was also supported, in part, by NIAMS grants (AR053607, AR056090 and AR059364); and NIA grant AG040013.
• Keywords: Rheumatology; ESTROGEN DEFICIENCY; KAPPA-B LIGAND; Science & Technology; SECRETED OSTEOCLASTOGENIC FACTOR; RHEUMATOID-ARTHRITIS; IN-VIVO; RECEPTOR ACTIVATOR; MASS; PARATHYROID-HORMONE; ANABOLIC ACTIVITY; MICE; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

Objective: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by severe joint erosion and systemic osteoporosis. Chronic T cell activation is a hallmark of RA, and agents that target the CD28 receptor on T cells, which is required for T cell activation, are being increasingly used as therapies for RA and other inflammatory diseases. Lymphocytes play complex roles in the regulation of the skeleton, and although activated T cells and B cells secrete cytokines that promote skeletal decline, under physiologic conditions lymphocytes also have key protective roles in the stabilization of skeletal mass. Consequently, disruption of T cell costimulation may have unforeseen consequences for physiologic bone turnover. This study was undertaken to investigate the impact of pharmacologic CD28 T cell costimulation blockade on physiologic bone turnover and structure. Methods: C57BL6 mice were treated with CTLA-4Ig, a pharmacologic CD28 antagonist or with irrelevant control antibody (Ig), and serum biochemical markers of bone turnover were quantified by enzyme-linked immunosorbent assay. Bone mineral density and indices of bone structure were further measured by dual x-ray absorptiometry and micro-computed tomography, respectively, and static and dynamic indices of bone formation were quantified using bone histomorphometry. Results: Pharmacologic disruption of CD28 T cell costimulation in mice significantly increased bone mass and enhanced indices of bone structure, a consequence of enhanced bone formation, concurrent with enhanced secretion of the bone anabolic factor Wnt-10b by T cells. Conclusion: Inhibition of CD28 costimulation by CTLA-4Ig promotes T cell Wnt-10b production and bone formation and may represent a novel anabolic strategy for increasing bone mass in osteoporotic conditions.