Mitigating inflammatory bone loss in post-menopausal osteoporosis via targeting the IL-9 producing osteoclastogenic Th9 cells

Recent discoveries have established the pivotal role of IL-9-secreting Th9 cells in a wide spectrum of inflammatory and autoimmune diseases. However, little is known about how Th9 cells contribute to the etiology of inflammatory bone loss in post-menopausal osteoporosis (PMO). We observed that IL-9 has a pathological impact on inflammatory bone loss in ovariectomized (Ovx) mice. Our in vivo temporal kinetics analysis further revealed that estrogen deprivation increased the release of IL-9 from Th which in turn enhances the IL-17-producing Th17 cells. Both ex vivo and in vivo studies corroborated these findings in Ovx mice, as estrogen diminishes IL-9s effect on the differentiation of Th17 cells as well as the potential of Th9 cells to produce IL-9. Mechanistically, Th9 cells in an IL-9-dependent manner enhance osteoclastogenesis and thereby establish themselves as a novel and independent osteoclastogenic Th subset. Blocking IL-9 improves bone health in Ovx mice by inhibiting the differentiation and function of both osteoclasts and Th9/Th17 cells. Our clinical findings further attested to the osteoporotic role of Th9 cells in post-menopausal osteoporotic human subjects. Collectively, our study establishes IL-9-secreting Th cells as the critical regulator of bone loss observed in PMO and highlights the fundamental implications of IL-9/Th9 targeted immunotherapies as an innovative approach for the treatment of inflammatory bone loss observed in osteoporosis.