NK Cells: Natural Bone Killers?

RESEARCH HIGHLIGHTS OSTEOIMMUNOLOGY NK cells: natural bone killers? atural killer (NK) cells contribute in direct contact with each other in the findings, the authors observed that to the bone erosion characteristic presence of IL-15, the cultures produced PB CD56bright NK cells from healthy Nof rheumatoid arthritis (RA) by large numbers of round, multinucleated individuals were more potent than CD56dim inducing the differentiation of monocytes cells that expressed the osteoclast marker NK cells (and PB T cells from healthy into osteoclasts, according to new tartrate-resistant acid phosphatase donors) in inducing the formation of research by Söderström et al. published (TRAP). Staining confirmed that these osteoclasts from autologous PB monocytes. in Proceedings of the National Academy cells also expressed markers associated To investigate the role of NK cells in of Sciences. with functional resorbing osteoclasts. osteoclastogenesis in vivo, the authors Although osteoclasts have been Analysis of lacunar resorption on dentine turned to a mouse model of implicated as the cell type predominantly slices confirmed that the cells were capable RA, collagen-induced responsible for mediating periarticular of eroding bone substrates. arthritis (CIA). They first bone loss in RA, the immunological events A standard method of producing confirmed the presence underlying their formation at these sites osteoclasts from peripheral blood (PB) of RANKL+ NK cells in remain unclear. NK cells are known to monocytes in vitro involves two key the joints of DBA/1 mice be present in the inflamed synovium of cytokines involved in bone resorption, with CIA; notably, these patients with RA—representing up to macrophage-colony stimulating factor cells were found next 20% of all lymphocytes in the synovial (M-CSF) and receptor activator of NFκB to sites of bone erosion. fluid (SF)—from the early stages of the ligand (RANKL). However, SF NK Next, specific depletion of NK disease. In addition, a proportion of cells seem to be a more-efficient trigger cells in vivo by use of a polyclonal anti- these SF NK cells are found side-by-side for the formation of osteoclasts from asialo GM1 antibody (after immunization with monocytes, an arrangement that PB monocytes: coculture with IL-15- with type II collagen but before the onset presumably enables cell–cell interactions. activated SF NK cells produced more and of arthritis) was shown to dramatically To answer the question of whether larger TRAP+ osteoclasts than coculture reduce the signs of bone erosion. the interaction between NK cells and with exogenous M-CSF and RANKL. Interestingly, inflammation, pannus monocytes leads to the differentiation “Our findings indicate that NK cells are formation and synovitis were also of monocytes into osteoclasts, the very potent in driving the differentiation reduced in mice treated with the anti- investigators experimented with cells of monocytes into osteoclasts,” says asialo GM1 antibody, suggesting that isolated from the SF of patients with RA. Söderström. “The process is rapid and you NK cells have a pathogenic role not only “We set up coculture protocols between need few NK cells to do the job.” in bone destruction but also in other highly enriched SF monocytes and SF The authors demonstrated that SF manifestations of arthritis. Previous NK cells using a culture medium NK cells express both M-CSF and studies have shown that neutralization known previously to facilitate RANKL, and, additionally, that of RANKL in RA and in CIA reduces NK cell survival and prolonged coculture with IL-15 bone loss but with minimal effects expansion,” explains lead upregulated the expression on inflammation; the authors suggest author Kalle Söderström. of these factors. In further that distinct NK cell subsets might be “In this system, we tested experiments, the neutralization responsible for each of these processes, whether a low number of either M-CSF and RANKL with RANKL+ NK cells being primarily of NK cells and a high suppressed SF NK cell-induced involved in bone erosion. “We need to number of monocytes, close osteoclastogenesis. compare the efficacy of NK cells side-by- to the physiological ratio SF NK cells also express CD56 side with other SF cell subsets known to found in the inflamed joints and are phenotypically related to a trigger osteoclastogenesis in vitro,” says of RA patients, would trigger monocyte minor subset of PB CD56bright NK cells Söderström. “Future research in mice may differentiation towards osteoclasts.” found in both patients with RA and healthy involve generating mice with RANKL–/– With an NK-cell:monocyte ratio of 1:10, individuals. Upon stimulation with IL-15, NK cells.” in vitro cocultures were performed in the PB CD56bright NK cells excreted M-CSF Sarah Price presence or absence of interleukin (IL)-15, at levels similar to those of SF NK cells, a cytokine present in the RA synovium that although in both these cell groups the is known to regulate the differentiation and excretion of soluble RANKL was induced Original article Söderström, K. et al. Natural killer cells activation of NK cells. When NK cells and only with the highest dose of IL-15 trigger osteoclastogenesis and bone destruction in arthritis. Proc. Natl Acad. Sci. USA 107, 13028–13033 (2010) autologous CD14+ monocytes were placed (100 ng/ml). Consistent with these NATURE REVIEWS | RHEUMATOLOGY VOLUME 6 | SEPTEMBER 2010 | 495 © 2010 Macmillan Publishers Limited. All rights reserved.

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