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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1481699

Myeloid-specific deletion of autotaxin inhibits rheumatoid arthritis and osteoclastogenesis

Provisionally accepted
Gwangbeom Heo Gwangbeom Heo 1Sihyun Jeong Sihyun Jeong 1Soyeong Park Soyeong Park 1Su Jin Kim Su Jin Kim 1Yunna Lee Yunna Lee 1Seong Ji Woo Seong Ji Woo 2Kyunghwan Kim Kyunghwan Kim 3Byung-Hyun Park Byung-Hyun Park 2Sang Hoon Rhee Sang Hoon Rhee 4EUNOK IM EUNOK IM 1*
  • 1 Pusan National University, Busan, Republic of Korea
  • 2 Medical School, Chonbuk National University, Jeonju, North Jeolla, Republic of Korea
  • 3 Chungbuk National University, Cheongju, North Chungcheong, Republic of Korea
  • 4 Oakland University, Rochester, New York, United States

The final, formatted version of the article will be published soon.

    Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint swelling, pain, and bone remodeling. We previously reported that autotaxin (ATX) deficiency disrupts lipid rafts in macrophages. Lipid raft disruption results in the dysregulation of RANK signaling, which is crucial for osteoclastogenesis and the pathogenesis of RA. Therefore, we evaluated the effect of ATX deficiency on joint inflammation and osteoclast differentiation. A collagen-induced arthritis mouse model was used with myeloid lineage-restricted Atx-knockout (Atx ΔME/ΔME ) mice and DBA/1 mice treated with the ATX inhibitor PF-8380. Joint inflammation and bone erosion were visualized using hematoxylin and eosin staining and micro-computed tomography. Osteoclast differentiation was assessed by tartrate-resistant acid phosphatase staining. ATX deficiency suppressed joint inflammation, bone resorption, osteoclast differentiation, and pro-inflammatory protein expression in both Atx ΔME/ΔME mice and PF-8380-treated mice compared to controls. Mean disease score of Atx +/+ mice at the end of experiment was 3.813, but that of Atx ΔME/ΔME was 0.185 (p < 0.05). The differentiation of bone marrow-derived macrophages into osteoclasts was reduced in Atx ΔME/ΔME cells compared to Atx +/+ cells. ATX deficiency suppressed RANKL-induced phosphorylation of ERK and the interaction between RANK and TRAF6. ATX deficiency disrupted lipid rafts and dysregulated RANK distribution in RAW264.7 cells. Actin ring formation was also inhibited in Atx ΔME/ΔME osteoclasts. ATX deficiency suppressed RA and osteoclast differentiation by disrupting lipid rafts and altering the RANK signaling pathway. This suggests that ATX inhibition may be an effective strategy for developing new disease-modifying antirheumatic drugs.

    Keywords: Rheumatoid arthritis, autotaxin, lipid rafts, osteoclastogenesis, collagen-induced arthritis

    Received: 16 Aug 2024; Accepted: 29 Nov 2024.

    Copyright: © 2024 Heo, Jeong, Park, Kim, Lee, Woo, Kim, Park, Rhee and IM. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: EUNOK IM, Pusan National University, Busan, Republic of Korea

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