Parathyroid Hormone-related Peptide Promotes Cancer-induced Bone Pain Through Direct Sensory Neuron Activation and Osteoclast-mediated Mechanisms

Background/Aim: Breast, prostate, and head and neck cancers readily metastasize to the bone, often causing cancer-induced bone pain (CIBP). Osteoclast activation acidifies the tumor microenvironment, contributing to CIBP. This acidity is linked to parathyroid hormone-related peptide (PTHrP) produced by cancer cells. PTHrP upregulates acid-sensitive receptors in sensory neurons, but the underlying mechanisms remain unclear. Materials and Methods: We evaluated breast cancer-induced bone pain (BCIBP) in vitro using primary dorsal root ganglion (DRG) neurons and F11 neurons and in vivo using female C57BL/6 athymic nude mice injected with 4T1 breast cancer cells into the tibial bone marrow. Results: Female C57BL/6 athymic nude mice developed BCIBP, characterized by upregulated phosphorylated ERK1/2 (pERK1/2) and phosphorylated CREB (pCREB) in DRG neurons, molecular indicators of neuronal excitation. Treatment with PTHrP (7-34), a PTHrP antagonist, suppressed BCIBP, pERK1/2, and pCREB expression in the DRG of 4T1-injected mice, tibial osteoclast differentiation, and secondary bone-to-lung metastasis. The PTHrP antagonist inhibited BCIBP indirectly by suppressing osteoclasts. Conclusion: PTHrP not only promoted osteoclast-mediated bone destruction but also directly induced bone pain by acting on sensory neurons.