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- Title
Enhanced Immunoprotective Effects by Anti-IL-17 Antibody Translates to Improved Skeletal Parameters Under Estrogen Deficiency Compared With Anti-RANKL and Anti-TNF-α Antibodies.
- Authors
Tyagi, Abdul M; Mansoori, Mohd N; Srivastava, Kamini; Khan, Mohd P; Kureel, Jyoti; Dixit, Manisha; Shukla, Priyanka; Trivedi, Ritu; Chattopadhyay, Naibedya; Singh, Divya
- Abstract
ABSTRACT Activated T cell has a key role in the interaction between bone and immune system. T cells produce proinflammatory cytokines, including receptor activator of NF-κB ligand (RANKL), tumor necrosis factor α (TNF-α), and interleukin 17 (IL-17), all of which augment osteoclastogenesis. RANKL and TNF-α are targeted by inhibitors such as denosumab, a human monoclonal RANKL antibody, and infliximab, which neutralizes TNF-α. IL-17 is also an important mediator of bone loss, and an antibody against IL-17 is undergoing phase II clinical trial for rheumatoid arthritis. Although there are a few studies showing suppression of Th17 cell differentiation and induction of regulatory T cells (Tregs) by infliximab, the effect of denosumab remains poorly understood. In this study, we investigated the effects of anti-TNF-α, anti-RANKL, or anti-IL-17 antibody administration to estrogen-deficient mice on CD4+ T-cell proliferation, CD28 loss, Th17/Treg balance and B lymphopoesis, and finally, the translation of these immunomodulatory effects on skeletal parameters. Adult Balb/c mice were treated with anti-RANKL/-TNF-α/-IL-17 subcutaneously, twice a week, postovariectomy (Ovx) for 4 weeks. Animals were then autopsied; bone marrow cells were collected for FACS and RNA analysis and serum collected for ELISA. Bones were dissected for static and dynamic histomorphometry studies. We observed that although anti-RANKL and anti-TNF-α therapies had no effect on Ovx-induced CD4+ T-cell proliferation and B lymphopoesis, anti-IL-17 effectively suppressed both events with concomitant reversal of CD28 loss. Anti-IL-17 antibody reduced proinflammatory cytokine production and induced Tregs. All three antibodies restored trabecular microarchitecture with comparable efficacy; however, cortical bone parameters, bone biomechanical properties, and histomorphometry were best preserved by anti-IL-17 antibody, likely attributable to its inhibitory effect on osteoblast apoptosis and increased number of bone lining cells and Wnt10b expression. Based on the superior immunoprotective effects of anti-IL-17, which appears to translate to a better skeletal preservation, we propose beginning clinical trials using a humanized antibody against IL-17 for treatment of postmenopausal osteoporosis. © 2014 American Society for Bone and Mineral Research.
- Subjects
BONE marrow cells; IMMUNE system; ESTROGEN; HORMONE deficiencies; CYTOKINES; INFLAMMATORY mediators; LYMPHOCYTES; IMMUNOGLOBULINS
- Publication
Journal of Bone & Mineral Research, 2014, Vol 29, Issue 9, p1981
- ISSN
0884-0431
- Publication type
Article
- DOI
10.1002/jbmr.2228