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Abstract
Multiple myeloma osteolytic disease is caused by an uncoupled bone-remodelling process with an increased osteoclast activity. Disease development relies on interactions between myeloma cells and bone marrow stromal cells. Recent findings suggest a role for glycan-binding proteins in myeloma microenvironment. Here, we investigated lectins involved in osteoclastogenesis and their role in myeloma bone disease. Microarray data analysis showed a lower expression of galectin-1 (gal-1) in mature osteoclasts compared to monocytic progenitor cells, confirmed at the RNA and protein levels in osteoclast cultures. Confocal microscopy showed that gal-1 localised predominantly in the sealing zone of mature osteoclasts. Although equal differentiated-osteoclast numbers, gal-1−/− osteoclasts showed a higher resorption activity compared to wild-type controls. Micro-computed tomography showed an aberrant bone phenotype with decreased bone densities in gal-1−/− mice. In vivo, tumour progression was faster in gal-1−/− mice and associated with a marked bone loss. Additionally, myeloma cells were found to decrease gal-1 expression in osteoclasts. Our results demonstrate that galectin-1 regulates osteoclast activity with an increased resorption by gal-1−/− osteoclasts and decreased bone densities in gal-1−/− mice. We observed an enhanced tumour development in gal-1−/− mice compared to wild-type mice, suggesting that galectin-1 has a functional role in stromal cells in myeloma microenvironment.
Highlights
Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow
Given the emerging role of lectins in osteoclast function, we performed a gene set enrichment analysis (GSEA) with a custom gene set for carbohydrate-binding proteins in publicly available microarray data of primary bone marrow monocyte-derived osteoclast differentiation
This confirmed that galectin-1 mRNA and protein levels were decreased in mature osteoclasts compared to monocytes (Figure 1C; complete WB: Figure S3)
Summary
Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow. Multiple myeloma bone disease (MMBD) is a hallmark of MM and characterised by both reduced bone formation and increased bone resorption, the latter due to an activation of osteoclast activity. Interactions between myeloma cells and bone marrow stromal cells are essential for the development of MMBD [1]. Recent data support a role for the glycan-binding protein galectin-1 in both myeloma cells and in the MM microenvironment. Galectin-1 stimulates angiogenesis and supports tumour cell proliferation in MM [2]. It has been identified as an extracellular matrix (ECM)-associated protein that is more abundant in the MM microenvironment [3]
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