Background/Purpose

Proinflammatory cytokines play an important role in bone destruction in rheumatoid arthritis (RA), as inferred by the efficacy of biologics. Previously, we reported that mouse osteoclast-like cells were induced, both in vitro and in vivo, by a combination of TNFα and IL-6 from bone marrow-derived monocytes/macrophages. Herein, we examined the differentiation, function, and regulation of osteoclast-like cells that were induced by the combination of TNFα and IL-6 from human CD14⁺monocytes.

Methods

Human CD14⁺ monocytes were cultured with IL-6, TNFα, or TNFα plus IL-6. Pit formation assay on dentine slices was performed to assess the bone-resorbing activity. The expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is the master regulatory transcription factor for osteoclast differentiation, was detected by a western blot analysis. The effects of osteoprotegerin (OPG), a decoy receptor for RANKL, NFAT inhibitor tacrolimus, or JAK inhibitor tofacitinib were examined.

Results

The tartrate-resistant acid phosphatase positive multinucleated osteoclast-like cells were induced by the combination of TNFα and IL-6 from human CD14⁺ monocytes in a dose-dependent manner. These osteoclast-like cells had bone resorption activity on dentin slices. The differentiation of conventional osteoclasts induced by RANKL from CD14⁺ monocytes was inhibited by OPG, whereas that of our osteoclast-like cells was not. Expression of NFATc1 was upregulated by the combination of TNFα and IL-6 compared with TNFα or IL-6 alone. In addition, differentiation of the osteoclast-like cells from CD14⁺monocytes was completely inhibited by tacrolimus. On the other hand, tofacitinib blocked the differentiation of the osteoclast-like cells through the JAK signaling pathway.

Conclusion

Osteoclast-like cells with bone resorption activity were induced by culturing human CD14⁺ monocytes with the combination of TNFα and IL-6. These results indicate that not only osteoclasts, but also osteoclast-like cells may be involved in the pathogenic mechanism of inflammatory bone destruction, such as RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/human-cd14-monocytes-stimulated-with-a-combination-of-tnf%ce%b1-and-il-6-differentiate-into-osteoclast-like-cells-with-bone-resorption-activity/