Characterization and Function of Tumor Necrosis Factor and Interleukin‐6–Induced Osteoclasts in Rheumatoid Arthritis

Abstract

Objective We have previously reported that stimulation of mouse bone marrow–derived macrophages with tumor necrosis factor (TNF) and interleukin‐6 (IL‐6) induces differentiation of osteoclast‐like cells. We undertook this study to clarify the characterization and function of human TNF and IL‐6–induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors. Methods Peripheral blood monocytes were cultured with a combination of TNF and IL‐6, TNF alone, IL‐6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL‐6–induced osteoclasts or RANKL‐induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole‐body bone mineral density (BMD) was examined. Results Peripheral blood monocytes stimulated with a TNF and IL‐6–induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL‐6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL‐6–induced osteoclast formation. Expression levels of IL1β, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL‐6–induced osteoclasts, but not in RANKL‐induced osteoclasts. The number of TNF and IL‐6–induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL‐induced osteoclast numbers negatively correlated with the whole‐body BMD of the same patients. Conclusion Our results demonstrate that TNF and IL‐6–induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA.

Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis

“…Interestingly, whereas bone absorption activity cannot be abolished in mice with STAT3 conditional knockout, treatment with JAK inhibitor or MEK inhibitor achieves this [104]. Furthermore, the number of osteoclasts induced ex vivo from RA patient PBMCs with TNF and IL-6 is positively correlated with the host patient modified total Sharp score [105]. IL-17 A also promotes MMP production in chondrocytes [106].…”

AnARHGAP25variant links aberrantRac1function to early‐onset skeletal fragility

“…(55,56) Accordingly, Huck et al (57) found that deletion of Rac1, exclusively at preosteoblastic stage, leads to decreased osteoblast proliferation and increased apoptosis, and in vivo deletion of Rac1 in mice results in decreased histomorphometric measures of osteoblast function, osteoid thickness, and BMD, which could be mediated through WNT signaling, as demonstrated by Wan et al (58) Because macrophages are an important source of inflammatory cytokines, it is also possible that some of the ARHGAP25 variant's negative effects on bone homeostasis could be indirect and mediated by abnormal production of such cytokines. (59) The skeletal phenotype of the Finnish family reported here could, therefore, result from defects in both osteoclast and osteoblast function.…”

Maternal High-Fat Diet Promotes Abdominal Aortic Aneurysm Expansion in Adult Offspring by Epigenetic Regulation of IRF8-Mediated Osteoclast-like Macrophage Differentiation

“…Yokota et al, have recently shown that the TNF-α treatment of human peripheral monocytes induced abundant TRAP-positive cells despite only a few multinucleated cells compared with the RANKL treatment [ 37 ]. In contrast, TNF-α-induced osteoclast-like macrophages highly expressed MMP3 mRNA compared with RANKL-induced osteoclasts.…”