Effect of IL-15 and Natural Killer Cells on Osteoclasts and Osteoblasts in a Mouse Coculture

Takeda, Hiroaki; Kikuchi, Takeshi; Soboku, Kyoko; Okabe, Iichiro; Mizutani, Hiroki; Mitani, Akio; Ishihara, Yuichi; Noguchi, Toshihide

doi:10.1007/s10753-013-9782-0

Cited by 46 publications

(46 citation statements)

References 40 publications

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“…B ), we refer to them as effector memory T cells (T EM ). IL‐15 has also been shown to directly regulate osteoclasts and osteoblasts, either alone or in combination with RANKL . Together with the CTX time course (Fig.…”

Section: Discussionmentioning

confidence: 78%

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

Cline-Smith

Axelbaum

Shashkova

et al. 2020

Journal of Bone and Mineral Research

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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.

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Section: Discussionmentioning

confidence: 78%

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

Cline-Smith

Axelbaum

Shashkova

et al. 2020

Journal of Bone and Mineral Research

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“…In human, IL‐15 was shown to drive osteoclast formation from monocyte precursors, but only in the presence of RA synovial NK cells, which up‐regulate both M‐CSF and membrane RANKL in response to IL‐15 . Moreover, a recent study showed that IL‐15 stimulates osteoblast apoptosis in mouse bone marrow cell cultures via activation of NK cells, again suggesting that IL‐15 is an inflammatory bone destructive factor . In fact, we are not aware of any reports indicating that IL‐15 may also display anti‐osteoclastogenic effects in vitro , and as targeting IL‐15R in vivo reduces disease progression and bone erosion in a mouse model of human RA, it is reasonable to conclude that the main role for IL‐15 on bone is to favour enhanced erosion.…”

Section: Discussionmentioning

confidence: 96%

Interleukin‐15‐activated natural killer cells kill autologous osteoclasts via LFA‐1, DNAM‐1 and TRAIL, and inhibit osteoclast‐mediated bone erosion in vitro

et al. 2015

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Osteoclasts reside on bone and are the main bone resorbing cells playing an important role in bone homeostasis, while natural killer (NK) cells are bone-marrow-derived cells known to play a crucial role in immune defence against viral infections. Although mature NK cells traffic through bone marrow as well as to inflammatory sites associated with enhanced bone erosion, including the joints of patients with rheumatoid arthritis, little is known about the impact NK cells may have on mature osteoclasts and bone erosion. We studied the interaction between human NK cells and autologous monocyte-derived osteoclasts from healthy donors in vitro. We show that osteoclasts express numerous ligands for receptors present on activated NK cells. Co-culture experiments revealed that interleukin-15-activated, but not resting, NK cells trigger osteoclast apoptosis in a dose-dependent manner, resulting in drastically decreased bone erosion. Suppression of bone erosion requires contact between NK cells and osteoclasts, but soluble factors also play a minor role. Antibodies masking leucocyte function-associated antigen-1, DNAX accessory molecule-1 or tumour necrosis factor-related apoptosis-inducing ligand enhance osteoclast survival when co-cultured with activated NK cells and restore the capacity of osteoclasts to erode bone. These results suggest that interleukin-15-activated NK cells may directly affect bone erosion under physiological and pathological conditions.

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“…39 In addition, IL-15 stimulates apoptosis of osteoblasts via activation of NK cells by Caspase3. 40 Strikingly, in the report, we first proved that GLP2 exerts its effect in part through the upregulation of iNOS expression. Our present approaches provided an unequirocal evidence for critical suppressor roles of the GLP2 in the osteoclasgenesis and supported the notion that GLP2 may be an alternative bona fide inhibiting factor of osteoporosis.…”

Section: Discussionmentioning

confidence: 92%

Glucagon‐like peptide 2 decreases osteoclasts by stimulating apoptosis dependent on nitric oxide synthase

Lü

2018

Cell Proliferation

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Effect of IL-15 and Natural Killer Cells on Osteoclasts and Osteoblasts in a Mouse Coculture

Cited by 46 publications

References 40 publications

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

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

Interleukin‐15‐activated natural killer cells kill autologous osteoclasts via LFA‐1, DNAM‐1 and TRAIL, and inhibit osteoclast‐mediated bone erosion in vitro

Glucagon‐like peptide 2 decreases osteoclasts by stimulating apoptosis dependent on nitric oxide synthase

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