Ovariectomy Activates Chronic Low-Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice

Abstract

The loss of estrogen (E2) initiates a rapid phase of bone loss leading to osteoporosis in one‐half of postmenopausal women, but the mechanism is not fully understood. Here, we show for the first time how loss of E2 activates low‐grade inflammation to promote the acute phase of bone catabolic activity in ovariectomized (OVX) mice. E2 regulates the abundance of dendritic cells (DCs) that express IL‐7 and IL‐15 by inducing the Fas ligand (FasL) and apoptosis of the DC. In the absence of E2, DCs become long‐lived, leading to increased IL‐7 and IL‐15. We find that IL‐7 and IL‐15 together, but not alone, induced antigen‐independent production of IL‐17A and TNFα in a subset of memory T cells (TMEM). OVX of mice with T‐cell–specific ablation of IL15RA showed no IL‐17A and TNFα expression, and no increase in bone resorption or bone loss, confirming the role of IL‐15 in activating the TMEM and the need for inflammation. Our results provide a new mechanism by which E2 regulates the immune system, and how menopause leads to osteoporosis. The low‐grade inflammation is likely to cause or contribute to other comorbidities observed postmenopause. © 2020 American Society for Bone and Mineral Research.

Absence of αβ T cells accelerates disuse bone loss in male mice after spinal cord injury

“…These findings in the T cell–deficient mice are surprising and seem to be distinct to disuse bone loss and to contrast the role of T cells reported in nearly all local and systemic conditions associated with bone loss. For example, T cells have been proposed to be instigators of bone damage in rheumatoid arthritis, adjuvant arthritis, alveolar gingivitis and periodontal diseases, inflammation, lipid‐induced bone loss, Crohn's disease, irritable bowel disease, hyperparathyroidism, and estrogen deficiency 13–27 . Consistently, pharmacologic suppression or depletion or genetic ablation of T cells attenuated the disease‐specific bone loss 13–27 .…”

“…In this regard, several investigations identified T cells as major promoters of bone damage in diverse disease conditions and models, and that pharmacologic T cell suppression or depletion, or genetic ablation attenuates the disease‐specific bone loss 13–27 . Importantly, studies performed on humans and mice demonstrated reduced T cell number, T cell suppression, 28–32 or the presence of autoreactive T cells after SCI 33,34 .…”

Osteoporosis: Pathophysiology and therapeutic options

“…However, an important link between estrogen loss, T-cell-dependent inflammation, and osteoporosis has been unraveled only recently. Cline-Smith et al for the first time described a molecular mechanism by which estrogen loss promotes a low-grade inflammation by T-cells during the acute phase of bone loss in ovariectomized mice (Cline-Smith et al, 2020[ 29 ]). They provide data suggesting a central role of bone marrow dendritic cells (BMDCs) in the induction of proinflammatory cytokines producing T-cells.…”

“…IL-7 and IL-15, in turn, induces antigen-independent production of IL-17A and TNF in a subset of memory T cells (T MEM ). Further, a crucial role of the suggested pathway in OVX associated bone loss was confirmed by showing that T-cell-specific ablation of IL15RA prevented IL-17A and TNF expression and an increase in bone resorption or bone loss after OVX (Cline-Smith et al, 2020[ 29 ]). Interestingly, the authors speculate that a crucial role of the activation of T MEM in postmenopausal bone loss may provide an explanation for varying susceptibilities to develop osteoporosis within a population.…”

“…Interestingly, the authors speculate that a crucial role of the activation of T MEM in postmenopausal bone loss may provide an explanation for varying susceptibilities to develop osteoporosis within a population. Varying levels of T MEM in individuals reflect different lifetime exposures to commensal and pathogenic microbes and might be associated with higher or lower levels of TNFα and IL-17A and in consequence of bone loss induced after menopause (Cline-Smith et al, 2020[ 29 ]).…”