MassIVE MSV000089119

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The Checkpoint Inhibitor PD-1H/VISTA Controls Osteoclast-Mediated Multiple Myeloma Bone Disease

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Description

Multiple myeloma (MM) bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 (MMP-13) as a novel MM-derived fusogen that, in turn, induces osteoclast activation independent of its proteolytic activity. While the mechanism by which the metalloprotease signals osteoclasts has remained the subject of conjecture, we now identify the checkpoint protein, programmed death-1 homolog (PD-1H/VISTA), as the bona fide MMP-13 receptor expressed on both pre- and mature osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-induced upregulation of ERK1/2-NFATc1-DC-STAMP signaling, the induction of osteoclast fusion and the increase in bone-resorptive activity. Further studies revealed that the intracellular domain of PD-1H interacts with the actin cytoskeleton of OCLs and plays a necessary role in supporting c-Src activation as well as sealing zone formation. The critical role of PD-1H in the development of lytic bone lesions in MM was confirmed using a Pd-1h-/- myeloma bone disease mouse model wherein MM cells injected into Pd-1h-/-Rag2-/- results in attenuated bone destruction relative to Pd-1hwtRag2-/- mice. Our findings identify a novel role for PD-1H in bone biology outside of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a novel approach for the treatment of MM-associated osteolysis. [doi:10.25345/C5251FP6G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Multiple Myeloma ; MMP-13 ; Synapt G2 HDMS ; osteolysis ; PD-1H/VISTA ; binding partners ; pulldown ; ion mobility ; Q Exactive HF ; label free

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Principal Investigators:
(in alphabetical order) 		Lewis M. Brown, Columbia University, United States
Suzanne Lentzsch, Vagelos College of Physicians and Surgeons, Columbia University, United States
Submitting User: proteomics2_columbia
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