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  3. JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors

JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors

  • Inflamm Regen. 2023 Mar 3;43(1):18. doi: 10.1186/s41232-023-00268-4.
Shinya Yari 1 2,  Junichi Kikuta 3 4 5,  Hotaka Shigyo 1,  Yu Miyamoto 1 2,  Daisuke Okuzaki 2 6,  Yuki Furusawa 7,  Masafumi Minoshima 8,  Kazuya Kikuchi 2 8,  Masaru Ishii 9 10 11
Affiliations

Affiliations

  • 1 Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, 565-0871, Japan.
  • 2 WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan.
  • 3 Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, 565-0871, Japan. [email protected].
  • 4 WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan. [email protected].
  • 5 Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan. [email protected].
  • 6 Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • 7 AbbVie GK, Medical Affairs, Tokyo, Japan.
  • 8 Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Osaka, Japan.
  • 9 Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, 565-0871, Japan. [email protected].
  • 10 WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan. [email protected].
  • 11 Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan. [email protected].
PMID: 36869390 DOI: 10.1186/s41232-023-00268-4
Abstract

Background: Rheumatoid arthritis (RA) is characterized by chronic inflammation and resultant cartilage/bone destruction because of aberrantly activated osteoclasts. Recently, novel treatments with several Janus kinase (JAK) inhibitors have been shown to successfully ameliorate arthritis-related inflammation and bone erosion, although their mechanisms of action for limiting bone destruction remain unclear. Here, we examined the effects of a JAK Inhibitor on mature osteoclasts and their precursors by intravital multiphoton imaging.

Methods: Inflammatory bone destruction was induced by local injection of lipopolysaccharides into transgenic mice carrying reporters for mature osteoclasts or their precursors. Mice were treated with the JAK Inhibitor, ABT-317, which selectively inhibits the activation of JAK1, and then subjected to intravital imaging with multiphoton microscopy. We also used RNA sequencing (RNA-Seq) analysis to investigate the molecular mechanism underlying the effects of the JAK Inhibitor on osteoclasts.

Results: The JAK Inhibitor, ABT-317, suppressed bone resorption by blocking the function of mature osteoclasts and by targeting the migratory behaviors of osteoclast precursors to the bone surface. Further exhaustive RNA-Seq analysis demonstrated that CCR1 expression on osteoclast precursors was suppressed in the JAK inhibitor-treated mice; the CCR1 Antagonist, J-113863, altered the migratory behaviors of osteoclast precursors, which led to the inhibition of bone destruction under inflammatory conditions.

Conclusions: This is the first study to determine the pharmacological actions by which a JAK Inhibitor blocks bone destruction under inflammatory conditions; this inhibition is beneficial because of its dual effects on both mature osteoclasts and immature osteoclast precursors.

Keywords

Cell migration; Chemokine; Inflammatory bone destruction; Intravital imaging; JAK inhibitor; Osteoclast.

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