Katharina F. Kubatzky

Interleukin (IL)‐9 is an emerging player in the pathogenesis of various chronic inflammatory diseases including bone disorders like rheumatoid arthritis (RA) and psoriatic arthritis. Recently, IL‐9 was shown to enhance the osteoclast formation and their function in RA. However, the mechanisms by which IL‐9 influences osteoclastogenesis are not known. Therefore, in this study we aimed to unravel the direct and indirect ways by which IL‐9 can influence osteoclast formation. We used mouse bone marrow precursor cells for checking the effect of IL‐9 on osteoclast differentiation and its function. Next, IL‐9 induced signalling pathway were checked in the process of osteoclastogenesis. T cells play an important role in enhancing osteoclastogenesis in inflammatory conditions. We used splenic T cells to understand the impact of IL‐9 on the functions of T effector (Teff) and regulatory T (Treg) cells. Furthermore, the effect of IL‐9 mediated modulation of the T cell response on osteoclasts was checked using a coculture model of T cells with osteoclast precursors. We showed that IL‐9 enhanced osteoclast formation and its function. We found that IL‐9 activates STAT3, P38 MAPK, ERK1/2, NFκB and we hypothesize that it mediates the effect on osteoclastogenesis by accelerating mitochondrial biogenesis. Additionally, IL‐9 was observed to facilitate the functions of pro‐osteoclastogenic IL‐17 producing T cells, but inhibits the function of anti‐osteoclastogenic Treg cells. Our observations suggest that IL‐9 can influence osteoclastogenesis directly by modulating the signalling cascade in the precursor cells; indirectly by enhancing IL‐17 producing T cells and by reducing the functions of Treg cells.