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

Jing Fu, Shirong Li, Huihui Ma, Jun Yang, Gabriel M. Pagnotti, Lewis M. Brown, Stephen J. Weiss, Markus Y. Mapara and Suzanne Lentzsch ()
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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
Jun Yang: Columbia University Irving Medical Center, Department of Medicine
Gabriel M. Pagnotti: Indiana University
Lewis M. Brown: Columbia University
Stephen J. Weiss: University of Michigan
Markus Y. Mapara: Columbia University Irving Medical Center, Department of Medicine
Suzanne Lentzsch: Columbia University Irving Medical Center, Department of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39769-8

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