IL‐17 mediates estrogen‐deficient osteoporosis in an Act1‐dependent manner

Abstract

Estrogen-deficient osteoporosis may be an inflammatory disorder and we therefore asked if IL-17 participates in its pathogenesis. Deletion of the principal IL-17 receptor (IL-17RA) protects mice from ovariectomy (OVX)-induced bone loss. Further supporting a central role of IL-17 in its pathogenesis, OVX-induced osteoporosis is prevented by a blocking antibody targeting the cytokine. IL-17 promotes osteoclastogenesis by stimulating RANK ligand (RANKL) expression by osteoblastic cells, mediated by the IL-17RA SEFIR/TILL domain. Estrogen deprivation, however does not enhance IL-17RA mRNA expression by osteoblasts or in bone, but augments that of Act1, an IL17RA-interacting protein and signaling mediator. Similar to IL-17RA−/− mice, those lacking Act1 are protected from OVX-induced bone loss. Also mirroring IL-17RA-deficiency, absence of Act1 in osteoblasts, but not osteoclasts, impairs osteoclastogenesis via dampened RANKL expression. Transduction of WT Act1 into Act1−/− osteoblasts substantially rescues their osteoclastogenic capacity. The same construct, however, lacking its E3 ligase U-box or its SEFIR domain, which interacts with its counterpart in IL-17RA, fails to do so. Estrogen deprivation, therefore, promotes RANKL expression and bone resorption in association with upregualtion of the IL-17 effector, Act1, supporting the concept that post-menopausal osteoporosis is a disorder of innate immunity.

Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction

“…In fact, in a recent study we have observed reduced atherosclerotic plaque burden in female Apoe/TRAF3IP2 double knock-out mice fed a Western diet (52). In another study, TRAF3IP2 was shown to mediate estrogen-deficient osteoporosis (53), further supporting the hypothesis that female sex hormones may negatively regulate TRAF3IP2 expression via mechanisms yet to be investigated.…”

IL-17A and IL-23 cytokines and their relation with estrogen in post menopausal osteoporosis

“…Increased IL-17 levels were associated with decrease mineralization of bone. De Selm [17] observed that blocking IL-17 signaling prevents estrogen deficiency mediated osteoporosis by inhibiting osteoclastogenesis in animal model. Molnar et al [18] in his study on human subjects observed strong association of estrogen deficiency with elevated IL-17 level in post menopausal females.…”

Osteoimmunology and Its Implications for Transplantation

“…The discrepancy between reports from us and other attesting to a role of T cells (7,32,33,35,37,39,40) and that of Lee at al. (38) is likely explained by differences in the experimental design, the lack of B cells in some models, and compensatory mechanisms such as an increase in natural killer (NK) cells producing the osteoclastogenic factor IL-17 (41).…”

“…The differentiation of the Th17 subset of CD4þ cells is inhibited by estrogen via a direct effect mediated by ERa (42). The specific contribution of Th17 in ovx induced bone loss remains controversial as one study reported that IL-17R null mice are more susceptible to ovx induced bone loss than controls (43), while another group found mice lacking IL-17R and mice treated with anti IL-17 antibody to be protected against ovx induced bone loss (44). Because IL-17 signaling has been documented to produce bone loss only in the context of severe inflammation, the fact that it is an essential component of ovx induced bone loss is apparently surprising.…”