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.
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.
authors.affiliation: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Abdul M
authors.initials: AM
authors.lastname: Tyagi
authors.forename: Mohd N
authors.initials: MN
authors.lastname: Mansoori
authors.forename: Kamini
authors.initials: K
authors.lastname: Srivastava
authors.forename: Mohd P
authors.initials: MP
authors.lastname: Khan
authors.forename: Jyoti
authors.initials: J
authors.lastname: Kureel
authors.forename: Manisha
authors.initials: M
authors.lastname: Dixit
authors.forename: Priyanka
authors.initials: P
authors.lastname: Shukla
authors.forename: Ritu
authors.initials: R
authors.lastname: Trivedi
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology*; D038041:Lymphopoiesis / Q000187:drug effects; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000187:drug effects; D010052:Ovariectomy; D053245:RANK Ligand / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D016207:Cytokines; D004967:Estrogens; D018836:Inflammation Mediators; D020381:Interleukin-17; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha
keywords: B LYMPHOPOESIS; ESTROGEN DEFICIENCY; IMMUNE SYSTEM; PROINFLAMMATORY CYTOKINES; T CELLS