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Hypoxia promotes IL-32 expression in myeloma cells, and high expression is associated with poor survival and bone
Muhammad Zahoor1, Marita Westhrin2, Kristin Roseth Aass1,3
1Centre of Molecular Inflammation Research and.
Abstract:
Multiple myeloma (MM) is a hematologic cancer characterized by expansion of malignant plasma cells in the bone marrow. Most patients develop an osteolytic bone disease, largely caused by increased osteoclastogenesis. The myeloma bone marrow is hypoxic, and hypoxia may contribute to MM disease progression, including bone loss. Here we identified interleukin-32 (IL-32) as a novel inflammatory cytokine expressed by a subset of primary MM cells and MM cell lines. We found that high IL-32 gene expression in plasma cells correlated with inferior survival in MM and that IL-32 gene expression was higher in patients with bone disease compared with those without. IL-32 was secreted from MM cells in extracellular vesicles (EVs), and those EVs, as well as recombinant human IL-32, promoted osteoclast differentiation both in vitro and in vivo. The osteoclast-promoting activity of the EVs was IL-32 dependent. Hypoxia increased plasma-cell IL-32 messenger RNA and protein levels in a hypoxia-inducible factor 1α-dependent manner, and high expression of IL-32 was associated with a hypoxic signature in patient samples, suggesting that hypoxia may promote expression of IL-32 in MM cells. Taken together, our results indicate that targeting IL-32 might be beneficial in the treatment of MM bone disease in a subset of patients.
Insights
Interleukin-32 (IL-32) promotes bone loss in multiple myeloma (MM) by driving osteoclast differentiation. Targeting IL-32 may offer a new treatment strategy for MM patients with bone disease.
Area of Science:
- Hematology
- Oncology
- Cell Biology
Background:
- Multiple myeloma (MM) is a cancer of plasma cells causing bone marrow expansion and osteolytic bone disease.
- Bone loss in MM is linked to increased osteoclastogenesis and bone marrow hypoxia.
- Hypoxia may drive MM progression and bone loss.
Purpose of the Study:
- To investigate the role of interleukin-32 (IL-32) in MM bone disease.
- To determine the relationship between IL-32 expression, hypoxia, and MM progression.
Main Methods:
- Identified IL-32 in MM cells and measured its gene expression in patient samples.
- Assessed IL-32 secretion via extracellular vesicles (EVs).
- Evaluated the effect of IL-32 and EVs on osteoclast differentiation in vitro and in vivo.
- Investigated the impact of hypoxia on IL-32 expression via hypoxia-inducible factor 1α (HIF-1α).
Main Results:
- High IL-32 gene expression in MM cells correlated with poorer survival and bone disease.
- MM cell-derived EVs and recombinant IL-32 promoted osteoclast differentiation.
- Osteoclast promotion by EVs was dependent on IL-32.
- Hypoxia increased IL-32 levels in MM cells in a HIF-1α-dependent manner.
- High IL-32 expression was linked to a hypoxic signature in MM patients.
Conclusions:
- IL-32 is a novel inflammatory cytokine contributing to MM bone disease.
- IL-32 promotes osteoclastogenesis, exacerbating bone loss in MM.
- Hypoxia upregulates IL-32 in MM cells, potentially linking hypoxia to bone disease.
- Targeting IL-32 may be a therapeutic strategy for MM-related bone complications.
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