Inhibition of the ATG4-LC3 pathway suppressed osteoclast maturation

• Published in: Biochemical and biophysical research communications 2022-12, Vol.632, p.40-47
• Main Authors: Hiura, Fumitaka, Kawabata, Yuko, Aoki, Tsukasa, Mizokami, Akiko, Jimi, Eijiro
• Format: Article
• Language: English
• Subjects: ATG4B; Autophagy; LC3; Osteoclasts
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.09.065

Autophagy is a non-selective action in which cells degrade parts of themselves, reusing degraded cellular components. Among autophagy-related gene (ATG) family members, ATG4 proteins play crucial roles in the microtubule-associated protein 1 light chain 3 (LC3) phosphatidylethanolamine (PE) system which is essential for autophagosome maturation. Although autophagy has been shown to be involved in osteoclastic bone resorption, the role of ATG4/LC3 in bone resorption remains unclear. When mouse bone marrow cells were treated with various concentrations of NSC185058 (NSC), a specific inhibitor of ATG4B, 1 h prior to treatment with receptor activator of NF-κB ligand (RANKL) in the presence of macrophage colony stimulating factor (M-CSF), NSC inhibited osteoclastogenesis in a dose-dependent manner. Addition of NSC in the late stages of osteoclast differentiation suppressed multinucleation and reduced the expression of markers for mature osteoclasts such as Dc-stamp, Mmp9, and Ctsk. NSC also suppressed actin ring formation and pit formation in mature osteoclasts. When a periodontitis model involving eight-week-old male mice in which the right maxillary second molar had been ligated with silk thread was injected with or without NSC, alveolar bone resorption was suppressed by a decrease in the number of osteoclasts in the NSC-treated group. These results suggest that LC3 is important for the maturation of osteoclasts and that LC3 inhibition is a new therapeutic strategy for periodontal disease. •We examined the effect of the AGT4B inhibitor, NSC185058 on bone resorption.•NSC185058 inhibited RANKL-induced osteoclastogenesis.•NSC185058 induced the accumulation of RANKL-induced LC3-II.•NSC185058 treatment prevented bone loss by osteoclasts in periodontitis model.•NSC185058 may be a new option for the treatment of bone loss of periodontitis.