Sodium Danshensu alleviates bone cancer pain by inhibiting the osteoclast differentiation and CGRP expression

Context

The morbidity of bone cancer pain (BCP) is on the rise, yet current treatments have limited analgesic efficacy. Sodium Danshensu (SDSS), or sodium 3-(3,4-dihydroxyphenyl)-DL-lactate, exhibits anti-inflammatory, anti-osteoporotic properties. Current research shows that bone cancer pain is closely related to the development of osteoclasts.

Objective

To investigate the analgesic effects of SDSS on BCP in mice and explore the underlying mechanisms.

Materials & methods

Nociceptive behaviors in BCP mice were evaluated by paw withdrawal threshold (PWT) and limb using score (LUS). Network pharmacology, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, and molecular docking identified potential targets. Histological analyses, Western blot, RT-qPCR, ELISA, and immunofluorescence staining were performed on mice femurs.

Results

SDSS significantly increased PWT and LUS in BCP mice. Forty-three common targets were identified, with the estrogen signaling pathway showing the highest enrichment. Molecular docking analysis suggested a potential binding affinity between SDSS and ESRα. SDSS administration up-regulated ESRα expression and down-regulated RANKL, RANK, NFATc1, c-fos, TRAP, and Cathepsin K (CTSK). In addition, SDSS suppressed the abnormal increase of calcitonin gene-related peptide-positive (CGRP⁺) neural budding and expression in nerve endings, effects which were reversed by ESRa inhibitor ICI-182780.

Conclusions

SDSS relieves bone cancer pain by inhibiting osteoclast activity, providing a potential new drug option for cancer pain patients.