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The checkpoint inhibitor PD-1H/VISTA controls osteoclast-mediated multiple myeloma bone disease

Author

Listed:
  • Jing Fu

    (Columbia University Irving Medical Center, Department of Medicine)

  • Shirong Li

    (Columbia University Irving Medical Center, Department of Medicine)

  • Huihui Ma

    (Columbia University Irving Medical Center, Department of Medicine
    Columbia Center for Translational Immunology)

  • Jun Yang

    (Columbia University Irving Medical Center, Department of Medicine)

  • Gabriel M. Pagnotti

    (Indiana University
    University of Texas—MD Anderson Cancer Center)

  • Lewis M. Brown

    (Columbia University)

  • Stephen J. Weiss

    (University of Michigan)

  • Markus Y. Mapara

    (Columbia University Irving Medical Center, Department of Medicine
    Columbia Center for Translational Immunology)

  • Suzanne Lentzsch

    (Columbia University Irving Medical Center, Department of Medicine)

Abstract

Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h-/- myeloma bone disease mouse model wherein myeloma cells injected into Pd-1h-/-Rag2-/- results in attenuated bone destruction. Our findings identify a role of PD-1H in bone biology independent of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a potential approach for the treatment of myeloma associated osteolysis.

Suggested Citation

  • Jing Fu & Shirong Li & Huihui Ma & Jun Yang & Gabriel M. Pagnotti & Lewis M. Brown & Stephen J. Weiss & Markus Y. Mapara & Suzanne Lentzsch, 2023. "The checkpoint inhibitor PD-1H/VISTA controls osteoclast-mediated multiple myeloma bone disease," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39769-8
    DOI: 10.1038/s41467-023-39769-8
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    References listed on IDEAS

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    1. Robert J. Johnston & Linhui Julie Su & Jason Pinckney & David Critton & Eric Boyer & Arathi Krishnakumar & Martin Corbett & Andrew L. Rankin & Rose Dibella & Lynne Campbell & Gaelle H. Martin & Hadia , 2019. "VISTA is an acidic pH-selective ligand for PSGL-1," Nature, Nature, vol. 574(7779), pages 565-570, October.
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