Exosomal miR-484 from lung adenocarcinoma promotes osteoclastogenesis and osteolytic bone metastasis by targeting PECAM1.

Bone metastasis is a frequent and devastating complication in lung adenocarcinoma (LUAD), where excessive osteoclast activation drives osteolytic destruction and skeletal-related events. How tumor-derived exosomes reprogram osteoclast precursors to establish a bone-metastatic niche remains incompletely understood. Here, we identify an exosomal miR-484–platelet endothelial cell adhesion molecule-1 (PECAM1) axis that links LUAD to pathological osteoclastogenesis and osteolytic bone metastasis. Using a highly bone-tropic Lewis lung carcinoma (BM-LLC) model, we show that BM-LLC-derived exosomes are preferentially internalized by osteoclast precursors and are markedly enriched in miR-484. Exosomal transfer of miR-484 increases intracellular miR-484 in these precursor cells and directly suppresses PECAM1, a negative regulator of osteoclastogenesis. PECAM1 repression activates NFATc1 and c-Fos, up-regulates osteoclast markers (TRAP, CTSK, RANK), and promotes osteoclast differentiation and bone matrix degradation in vitro. Gain- and loss-of-function studies demonstrate that PECAM1 overexpression or miR-484 inhibition attenuates BM-LLC exosome–induced osteoclastogenesis, whereas PECAM1 knockdown phenocopies miR-484 and further amplifies osteoclast activation. In vivo, systemic administration of BM-LLC exosomes exacerbates osteolytic lesions and bone tumor burden without altering lung colonization, while therapeutic delivery of antagomiR-484 partly restores PECAM1 expression, suppresses osteoclastogenic signaling, and alleviates bone loss. Circulating exosomal miR-484 levels correlate with the severity of osteolysis, supporting its potential as a liquid biopsy biomarker. Collectively, our data define exosomal miR-484–mediated PECAM1 suppression as a critical mechanism by which LUAD cells remodel the bone microenvironment, and highlight the miR-484–PECAM1axis as a tractable target for preventing or treating osteolytic bone metastasis.