Antagonizing exosomal miR-18a-5p derived from prostate cancer cells ameliorates metastasis-induced osteoblastic lesions by targeting Hist1h2bc and activating Wnt/β-catenin pathway

More than 50%of prostate cancer(PCa)patients have bone metastasis with osteo-blastic lesions.MiR-18a-5p is associated with the development and metastasis of PCa,but it remains unclear whether it is involved in osteoblastic lesions.We first found that miR-18a-5p was highly expressed in the bone microenvironment of patients with PCa bone metastases.To address how miR-18a-5p affects PCa osteoblastic lesions,antagonizing miR-18a-5p in PCa cells or pre-osteoblasts inhibited osteoblast differentiation in vitro.Moreover,injection of PCa cells with miR-18a-5p inhibition improved bone biomechanical properties and bone mineral mass in vivo.Furthermore,miR-18a-5p was transferred to osteoblasts by exosomes derived from PCa cells and targeted the Hist1h2bc gene,resulting in Ctnnb1 up-regulation in the Wnt/β-catenin signaling pathway.Translationally,antagomir-18a-5p significantly improved bone biomechanical properties and alleviated sclerotic lesions from osteoblastic me-tastases in BALB/c nude mice.These data suggest that inhibition of exosome-delivered miR-18a-5p ameliorates PCa-induced osteoblastic lesions.