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Parathyroid Hormone-related Peptide Promotes Cancer-induced Bone Pain Through Direct Sensory Neuron Activation and
Yodai Hayashi1, Yusaku Noma1, Haruka Yoshinaga1
1Department of Maxillofacial Diagnostic and Surgical Science, Field of Oral and Maxillofacial Rehabilitation, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan.
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.
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