A 15-amino acid C-terminal peptide of beta-defensin-3 inhibits bone resorption by inhibiting the osteoclast differentiation and disrupting podosome belt formation

Human beta-defensin-3 (hbd3), which is secreted from cells in the skin, salivary gland, and bone marrow, exhibits antimicrobial and immunomodulatory activities. its c-terminal end contains a 15-amino acid polypeptide (hbd3-c15) that is known to effectively elicit antimicrobial activity. recently, certain antimicrobial peptides are known to inhibit osteoclast differentiation and, thus, we investigated whether hbd3-c15 hinders osteoclast differentiation and bone destruction to assess its potential use as an anti-bone resorption agent. hbd3-c15 inhibited the receptor activator of nuclear factor κb ligand (rankl)-induced osteoclast differentiation and formation of resorption pits. in addition, hbd3-c15 disrupted the formation of rankl-induced podosome belt which is a feature typically found in mature osteoclasts with bone-resorbing capacity. hbd3-c15 downregulated cortactin, cofilin, and vinculin, which are involved in the podosome belt formation. furthermore, bone loss induced by rankl was significantly reduced in a mouse calvarial implantation model that was treated with hbd3-c15. similar inhibitory effects were observed on the osteoclast differentiation and podosome belt formation induced by aggregatibacter actinomycetemcomitans lipopolysaccharide (aalps). concordantly, hbd3-c15 attenuated the resorption in the calvarial bone of aalps-implanted mouse. collectively, these results suggest that hbd3-c15 has an anti-bone resorption effect in developing osteoclasts and that this occurs via its disruption of podosome belt formation. hbd3-c15 could be a potential therapeutic agent for the inhibition of bone destruction.