Osteoporosis is the most prevalent metabolic bone disease that affects half the women in the sixth and seventh decade of life. Osteoporosis is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. Several factors contribute to osteoporosis in men and women. In women, menopause – the cessation of ovarian function, is one of the leading causes of primary osteoporosis. Over the past three decades there has been growing appreciation that the adaptive immune system plays a fundamental role in the development of postmenopausal osteoporosis, both in humans and in mouse models. In this review, we highlight recent data on the interactions between T cells and the skeletal system in the context of postmenopausal osteoporosis. Finally, we review recent studies on the interventions to ameliorate osteoporosis.
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.
Osteoimmunology arose from the recognition that cytokines produced by lymphocytes can affect bone homeostasis. We have previously shown that osteoclasts, cells that resorb bone, act as antigen-presenting cells. Cross-presentation of antigens by osteoclasts leads to expression of CD25 and FoxP3, markers of regulatory T-cells in the CD8 T-cells. Osteoclast-induced FoxP3+ CD8 T-cells (OC-iTcREG) suppress priming of CD4 and CD8 T-cells by dendritic cells. OC-iTcREG also limit bone resorption by osteoclasts, forming a negative feedback loop. Here we show that OC-iTcREG express concurrently T-bet and Eomesodermin (Eomes) and IFN-γ. Pharmacological inhibition of IκK blocked IFN-γ, T-bet and Eomes production by TcREG. Furthermore, we show using chromatin immunoprecipitation, NF-κB enrichment in the T-bet and Eomes promoter. We demonstrate that IFN-γ produced by TcREG is required for suppression of osteoclastogenesis and for degradation of tumor necrosis factor receptor-associated factor 6 (TRAF6) in osteoclast precursors. The latter prevents signaling by receptor activator of NF-κB ligand (RANKL) needed for osteoclastogenesis. Knockout of IFN-γ rendered TcREG inefficient in preventing actin ring formation in osteoclasts, a process required for bone resorption. TcREG generated in vivo using IFN-γ−/− T-cells had impaired ability to protect mice from bone resorption and bone loss in response to high-dose RANKL. The results of this study demonstrate a novel link between NF-κB signaling and induction of IFN-γ in TcREG and establish important role for IFN-γ in TcREG-mediated protection from bone loss.
A number of studies in model animal systems and in the clinic have established that RANKL promotes bone resorption. Paradoxically, we found that pulsing ovariectomized mice with low-dose RANKL suppressed bone resorption, decreased the levels of proinflammatory effector T cells and led to increased bone mass. This effect of RANKL is mediated through the induction of FoxP3+CD25+ regulatory CD8+ T cells (TcREG) by osteoclasts. Here, we show that pulses of low-dose RANKL are needed to induce TcREG, as continuous infusion of identical doses of RANKL by pump did not induce TcREG. We also show that low-dose RANKL can induce TcREG at 2, 3, 6, and 10 weeks after ovariectomy. Our results show that low-dose RANKL treatment in ovariectomized mice is optimal at once-per-month doses to maintain the bone mass. Finally, we found that treatment of ovariectomized mice with the Cathepsin K inhibitor odanacatib also blocked TcREG induction by low-dose RANKL. We interpret this result to indicate that antigens presented to CD8+ T cells by osteoclasts are derived from the bone protein matrix because Cathepsin K degrades collagen in the bone. Taken together, our studies provide a basis for using low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis.
A great achievement of modern medicine is the increased lifespan of the human population. Unfortunately, the comorbidities of aging have created a large economic and health burden on society. Osteoporosis is the most prevalent age-related disease. It is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. These fractures lead to disproportionally high mortality rate and a drastic decline in quality of life for those affected. While estrogen loss is one known trigger of osteoporosis, a number of recent studies have shown that osteoporosis is a multifactorial condition in both humans and rodent models. The presence or absence of certain factors are likely to determine which subset of the population develop osteoporosis. In this chapter, we review the factors that contribute to osteoporosis with an emphasis on its multifactorial nature and the therapeutic consequences.
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