The miR4261/PAMM axis in multiple myeloma promotes bone resorption

This study investigates the mechanisms underlying myeloma bone disease (MBD) in multiple myeloma (MM), focusing on myeloma cell-derived exosomes and liquid biopsy biomarkers to identify therapeutic targets for reducing osteoclast activity and enhancing bone homeostasis. Co-culture of OPM2, RPMI 8226, and NCI-H929 myeloma cell lines with THP-1 cells was employed to assess miR4261 and Perox iredoxin Activated in M-CSF-stimulated monocytes (PAMM) expression via RT-qPCR. Dual-luciferase assays confirmed miR4261 binding to the 3'-untranslated region (3'-UTR) of PAMM. THP-1 cells transfected with miR4261 mimics or shPAMM vectors, and treated with M-CSF and RANKL, exhibited enhanced osteoclast differentiation, as evaluated by TRAP staining and micro-CT analysis of bone mineral content (BMC) and tissue mineral content (TMC). Elevated miR4261 expression in MBD patients negatively correlated with PAMM expression, promoting bone resorption. Gene ontology-based gene set enrichment analysis (GO-GSEA) revealed downregulation of genes negatively regulating osteoclast differentiation in the shPAMM group. The miR4261/PAMM axis drives MBD by enhancing osteoclast activity, suggesting dual targeting of miR4261 and PAMM as a potential therapeutic strategy to mitigate bone destruction in MM.