Enhanced Immunoprotective Effects by Anti-IL-17 Antibody Translates to Improved Skeletal Parameters Under Estrogen Deficiency Compared With Anti-RANKL and Anti-TNF-[alpha] Antibodies

• Published in: Journal of bone and mineral research 2014-09, Vol.29 (9), p.1981
• Main Authors: Tyagi, Abdul M, Mansoori, Mohd N, Srivastava, Kamini, Khan, Mohd P, Kureel, Jyoti, Dixit, Manisha, Shukla, Priyanka, Trivedi, Ritu, Chattopadhyay, Naibedya, Singh, Divya
• Format: Article
• Language: English
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.2228

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-[kappa]B ligand (RANKL), tumor necrosis factor [alpha] (TNF-[alpha]), and interleukin 17 (IL-17), all of which augment osteoclastogenesis. RANKL and TNF-[alpha] are targeted by inhibitors such as denosumab, a human monoclonal RANKL antibody, and infliximab, which neutralizes TNF-[alpha]. 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-[alpha], 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-[alpha]/-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-[alpha] 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. [PUBLICATION ABSTRACT]