The Checkpoint Inhibitor Pd-1H/Vista Controls Osteoclast-Mediated Multiple Myeloma Bone Disease

Authors

Jing Fu
Shirong Li
Huihui Ma
Jun Yang
Gabriel M Pagnotti
Lewis M Brown
Stephen J Weiss
Markus Y Mapara
Suzanne Lentzsch

Publication Date

7-17-2023

Journal

Nature Communications

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.

Keywords

Animals, Mice, Bone and Bones, Carrier Proteins, Matrix Metalloproteinase 13, Multiple Myeloma, Osteoclasts, Osteolysis

DOI

10.1038/s41467-023-39769-8

PMID

37460553

PMCID

PMC10352288

PubMedCentral® Posted Date

7-17-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes