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CTLA-4Ig–Induced T Cell Anergy Promotes Wnt-10b Production and Bone Formation in a Mouse Model
Article first published online: 28 MAR 2014
Copyright © 2014 by the American College of Rheumatology
Arthritis & Rheumatology
Volume 66, Issue 4, pages 990–999, April 2014
How to Cite
Roser-Page, S., Vikulina, T., Zayzafoon, M. and Weitzmann, M. N. (2014), CTLA-4Ig–Induced T Cell Anergy Promotes Wnt-10b Production and Bone Formation in a Mouse Model. Arthritis & Rheumatology, 66: 990–999. doi: 10.1002/art.38319
Emory University and the Atlanta VAMC have filed a patent application for the use of CD28 modulators for bone anabolic activity.
- Issue published online: 28 MAR 2014
- Article first published online: 28 MAR 2014
- Accepted manuscript online: 27 JAN 2014 01:57PM EST
- Manuscript Accepted: 10 DEC 2013
- Manuscript Received: 1 NOV 2012
- VA Office of Research and Development
- Biomedical Laboratory Research and Development Service. Grant Number: 5I01BX000105
- NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS]). Grant Numbers: AR-053607, AR-056090, AR-059364
- National Institute on Aging. Grant Number: AG-040013
- NIH (NIAMS). Grant Number: P30-AR-46031
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.
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.
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.
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.