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Abstract Number: 1472

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

Kazuhiro Yokota1, Kojiro Sato2, Yoshimi Aizaki3, Shinya Tanaka4, Miyoko Sekikawa4, Noritsune Kozu5, Yuho Kadono4, Hiromi Oda6 and Toshihide Mimura7, 1Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan, 2Jichi Medical University, Tochigi, Japan, 3Saitama Medical University, Saitama, Japan, 4Department of Orthopaedic Surgery, Saitama Medical University, Saitama, Japan, 5Kozu Orthopaedic Clinic, Chiba, Japan, 6Department of Orthopaedic Surgery, National Hospital Organization Ibusuki Medical Center, Kagoshima, Japan, 7Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama, Japan

Meeting: ACR Convergence 2021

Keywords: bone biology, cytokines, osteoclastogenesis, RANKL, rheumatoid arthritis

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Session Information

Date: Tuesday, November 9, 2021

Title: Osteoarthritis & Joint Biology – Basic Science Poster (1468–1479)

Session Type: Poster Session D

Session Time: 8:30AM-10:30AM

Background/Purpose: We have previously reported that stimulation of mouse bone marrow–derived macrophages with a combination of tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) induces differentiation of osteoclast-like cells with bone resorption activity (Yokota K et al., Arthritis & Rheumatology 2014, 66:121-129). The present study aims to clarify the characterization and function of human TNFα and IL-6–induced osteoclasts using human peripheral blood cells collected from patients with rheumatoid arthritis (RA) or healthy donors. In addition, we also identify the differences in the molecular expression patterns between the novel TNFα and IL-6-induced osteoclasts and conventional RANKL-induced osteoclasts.

Methods: Human peripheral blood monocytes were cultured with a combination of TNFα and IL-6, TNFα alone, IL-6 alone, or RANKL, and their bone resorption ability were evaluated. Expression levels of nuclear factor of activated T cell (NFAT) c1, proinflammatory cytokines, matrix metalloproteinase-3 (MMP-3), and cathepsin K (CTSK) were analyzed. The effects of osteoprotegerin (OPG), NFAT inhibitor, and JAK inhibitor on these osteoclastogenesis were examined. Furthermore, we examined the relationship between the number of TNFα and IL-6–induced osteoclasts or RANKL-induced osteoclasts differentiated from peripheral blood mononuclear cells in patients with RA and the relationship, modified total Sharp score (mTSS) and whole-body bone mineral density (BMD).

Results: Peripheral blood monocytes stimulated with a combination of TNFα and IL-6 showed the ability to absorb bone matrix, which has been supposed to be the function of osteoclasts. The differentiation was not inhibited by the addition of OPG contrary to that of RANKL-induced ones. Stimulation with a combination of TNFα and IL-6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented this TNFα and IL-6–induced osteoclast formation. Expression levels of IL-1β, TNFα, and IL-12p40 were significantly increased in TNFα and IL-6–induced osteoclasts, but not in RANKL-induced osteoclasts. IL-1β up-regulated the differentiation of TNFα and IL-6–induced osteoclasts. The number of TNFα and IL-6–induced osteoclasts from patients with RA positively correlated with the mTSS, whereas RANKL-induced osteoclast numbers negatively correlated with the whole-body BMD of the same patients. The expression levels of MMP-3 were significantly higher in TNFα and IL-6-induced osteoclasts than in RANKL-induced osteoclasts. Conversely, the expression levels of CTSK were significantly higher in RANKL-induced osteoclasts than in TNFα and IL-6-induced osteoclasts.

Conclusion: Our results demonstrate that TNFα and IL-6–induced osteoclasts differentiate via RANKL-independent pathways and may contribute to the joint destruction in the inflammatory arthritis, such as RA.


Disclosures: K. Yokota, None; K. Sato, None; Y. Aizaki, None; S. Tanaka, None; M. Sekikawa, None; N. Kozu, None; Y. Kadono, None; H. Oda, None; T. Mimura, None.

To cite this abstract in AMA style:

Yokota K, Sato K, Aizaki Y, Tanaka S, Sekikawa M, Kozu N, Kadono Y, Oda H, Mimura T. Characterization and Function of Tumor Necrosis Factor α and Interleukin-6–Induced Osteoclasts in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/characterization-and-function-of-tumor-necrosis-factor-%ce%b1-and-interleukin-6-induced-osteoclasts-in-rheumatoid-arthritis/. Accessed .
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