Eeles Damien G, Hodge Jason M, Singh Preetinder P, Schuijers Johannes A, Grills Brian L, Gillespie Matthew T, Myers Damian E, Quinn Julian M W
MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia; Department of Human Biosciences, La Trobe University, Bundoora, VIC, Australia.
Barwon Biomedical Research, Department of Medicine, The Geelong Hospital, Geelong, VIC, Australia; School of Medicine, Deakin University, Geelong, VIC, Australia.
Mol Cell Endocrinol. 2015 Jan 5;399:259-66. doi: 10.1016/j.mce.2014.10.014. Epub 2014 Oct 18.
Osteoclasts are bone resorbing multinucleated cells (MNCs) derived from macrophage progenitors. IL-33 has been reported to drive osteoclastogenesis independently of receptor activator of NFκB ligand (RANKL) but this remains controversial as later studies did not confirm this. We found IL-33 clearly elicited functional dentine-resorbing osteoclast formation from human adult monocytes. However, monocytes from only 3 of 12 donors responded this way, while all responded to RANKL. Human cord blood-derived progenitors and murine bone marrow macrophages lacked an osteoclastogenic response to IL-33. In RAW264.7 cells, IL-33 elicited NFκB and p38 responses but not NFATc1 signals (suggesting poor osteoclastogenic responses) and formed only mononuclear tartrate-resistant acid phosphatase positive (TRAP(+)) cells. Since TGFβ boosts osteoclastogenesis in RAW264.7 cells we employed an IL-33/TGFβ co-treatment, which resulted in small numbers of MNCs expressing key osteoclast markers TRAP and calcitonin receptors. Thus, IL-33 possesses weak osteoclastogenic activity suggesting pathological significance and, perhaps, explaining previous conflicting reports.
破骨细胞是源自巨噬细胞祖细胞的骨吸收多核细胞（MNCs）。据报道，白细胞介素-33（IL-33）可独立于核因子κB受体活化因子配体（RANKL）驱动破骨细胞生成，但这一观点仍存在争议，因为后续研究并未证实这一点。我们发现，IL-33能明显诱导成人单核细胞形成具有功能性牙本质吸收能力的破骨细胞。然而，12名供体中只有3人的单核细胞有此反应，而所有供体的单核细胞对RANKL均有反应。人脐血来源的祖细胞和小鼠骨髓巨噬细胞对IL-33缺乏破骨细胞生成反应。在RAW264.7细胞中，IL-33可引发核因子κB和p38反应，但不引发活化T细胞核因子1（NFATc1）信号（提示破骨细胞生成反应较弱），且仅形成单核抗酒石酸酸性磷酸酶阳性（TRAP(+)）细胞。由于转化生长因子β（TGFβ）可促进RAW264.7细胞的破骨细胞生成，我们采用了IL-33/TGFβ联合处理，结果产生了少量表达关键破骨细胞标志物TRAP和降钙素受体的多核细胞。因此，IL-33具有较弱的破骨细胞生成活性，提示其具有病理意义，或许也能解释此前相互矛盾的报道。
