Abstract
Interleukin-7 (IL-7), which is required for the development and survival of T cells in the thymus and periphery, plays a role in joint destruction. However, it remains unclear how IL-7 affects osteoclast formation. Thus, we investigated the mechanism by which IL-7 induced osteoclast formation through IL-7 receptor α (IL-7Rα) in osteoclast precursors. We cultured peripheral blood mononuclear cells or synovial fluid mononuclear cells with IL-7 in the presence or absence of an appropriate inhibitor to analyze osteoclast formation. We also constructed IL-7Rα-expressing RAW264.7 cells to uncover the mechanism(s) by which IL-7 induced osteoclast formation differed from that of receptor activator of nuclear factor κB ligand (RANKL). We found that IL-7 induced osteoclast formation of human monocytes from peripheral blood or synovial fluid in a RANKL-independent and a signal transducer and activator of transcription 5 (STAT5)-dependent manner. IL-7-induced osteoclasts had unique characteristics, such as small, multinucleated tartrate-resistant acid phosphatase positive cells and no alterations even when RANKL was added after IL-7 pretreatment. RAW264.7 cells, if overexpressing IL-7Rα, also were able to differentiate into osteoclasts by IL-7 through a STAT5 signaling pathway. Furthermore, IL-7-induced osteoclast formation was repressed by inhibitors of the IL-7R signaling molecules Janus kinase and STAT5. Our findings demonstrate that IL-7 is a truly osteoclastogenic factor, which may induce osteoclast formation via activation of STAT5, independent of RANKL. We also suggest the possibility that an IL-7R pathway blocker could alleviate joint damage by inhibiting osteoclast formation, especially in inflammatory conditions.
Highlights
Bone is a dynamic tissue that changes its overall shape in response to physiological influences and mechanical forces, in a process called bone remodeling
On day 10, osteoclast differentiation from peripheral blood mononuclear cell (PBMC) by IL-7 was comparable to that from macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL) (Figure 1B), while osteoclast formation from synovial fluid mononuclear cell (SFMC) by IL-7, meaningful compared to the M-CSF control, was significantly lower than that induced by M-CSF and RANKL (Figure S1B in Supplementary Material)
The size of the multinucleated tartrate-resistant acid phosphatase (TRAP)+ cells by IL-7 was small, we found that the roughness of dentine pit formation by IL-7-induced osteoclasts was comparable with the pit formation by M-CSF- and RANKL-induced osteoclasts, regardless of whether the osteoclasts were derived from PBMCs or SFMCs (Figures 1C,D; Figures S1C,D in Supplementary Material)
Summary
Bone is a dynamic tissue that changes its overall shape in response to physiological influences and mechanical forces, in a process called bone remodeling. Osteoclasts, in both normal and pathological conditions, originate from the hematopoietic (monocyte/macrophage) lineage, which fuse to form active resorbing cells [reviewed in Ref. Receptor activator of nuclear factor κB ligand (RANKL) binds to its receptor (RANK) on osteoclast precursors and serves as an essential factor in osteoclast formation, participating in the regulation of bone remodeling; this ligand is counterbalanced by osteoprotegerin (OPG) [3]. RANKL is expressed by stromal cells, bone-lining cells, osteoblasts, and activated T cells [reviewed in Ref. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), which increase under pathological conditions, such as rheumatoid arthritis (RA) and osteoporosis, induce the expression of RANKL in osteoblasts and stromal cells, eventually enhancing osteoclast formation [5, 6]
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