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

ABSTRACT: 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.

INSTRUMENT(S): Synapt G2 HDMS, Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Suzanne Lentzsch Lewis M. Brown

PROVIDER: MSV000089119 | MassIVE | Thu Mar 24 07:46:00 GMT 2022

REPOSITORIES: MassIVE

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Project description:The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast formation and the occurrence of bone lesions are still unknown. Osteocytes regulate bone remodeling at least in part through the cell death and apoptosis triggering osteoclast recruitment and formation. In this study, firstly we shown that MM cells increased osteocyte death and affect their transcriptional profile evaluated by microarray analysis up-regulating osteoclastogenic cytokines as interleukin (IL)-11. Consistently we show that the conditioned media of human pre-osteocytes co-cultured with MM cells significantly increased osteoclastogenesis. To translate into a clinical perspective such in vitro evidences, we then performed histological analysis on bone biopsies obtained from MM patients, MGUS and healthy controls. We found a significant reduction in the number of viable osteocytes in MM patients as compared to controls. A significant negative correlation between the number of viable osteocytes and that of osteoclasts was also demonstrated. Moreover, as regards the skeletal involvement, we found that MM patients with bone lesions have a significant lower number of viable osteocyte than those without. Overall, our data suggest a role of osteocytic cell death in MM-induced osteoclast formation in vitro and MM bone disease in vivo in MM patients. This series of microarray experiments contains the gene expression profiles of HOB-01 osteocytes cultured alone and co-cultured with the JJN3 human myeloma cell line. 5 micrograms of total RNA was processed, and in accordance with the manufacturer's protocols, the fragmented biotin-labelled cRNA were hybridized on GeneChip Human Genome U133 Plus 2.0 Arrays (Affymetrix Inc.). The arrays were scanned using the Agilent GeneChip Scanner 3000 7G. The images were acquired using Affymetrix GeneChip Operating System (GCOS) 1.1 software and the probe level data converted to expression values using default GCOS1.1 scaling. Natural-scaled data are provided.

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

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