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

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2017-12, Vol.95 (12), p.1315-1325
• Main Authors: Park, Ok-Jin, Kim, Jiseon, Ahn, Ki Bum, Lee, Jue Yeon, Park, Yoon-Jeong, Kum, Kee-Yeon, Yun, Cheol-Heui, Han, Seung Hyun
• Format: Article
• Language: English
• Subjects: Aggregatibacter - chemistry; Amino acids; Animals; Antimicrobial activity; Antimicrobial agents; Antimicrobial peptides; beta-Defensins - chemistry; Biomedical and Life Sciences; Biomedicine; Bone growth; Bone loss; Bone marrow; Bone resorption; Bone Resorption - drug therapy; Bone Resorption - pathology; Cell Differentiation - drug effects; Chemical compounds; Cofilin; Disruption; Down-Regulation - drug effects; Human Genetics; Immunomodulation; Implantation; Internal Medicine; Lipopolysaccharides; Mice, Inbred C57BL; Molecular Medicine; NFATC Transcription Factors - metabolism; Original Article; Osteoclastogenesis; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Peptides; Peptides - pharmacology; Peptides - therapeutic use; Podosomes - drug effects; Podosomes - metabolism; Proto-Oncogene Proteins c-fos - metabolism; RANK Ligand - pharmacology; Salivary gland; Skin; TRANCE protein; Vinculin
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-017-1589-2

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. Key messages HBD3-C15 inhibits osteoclast differentiation and bone resorption capacity. HBD3-C15 disrupts the podosome belt formation in osteoclasts. HBD3-C15 alleviates the bone loss by RANKL or A. actinomycetemcomitans LPS in vivo.