Frontiers in Immunology (Apr 2023)

Inhibition of non-canonical NF-κB signaling suppresses periodontal inflammation and bone loss

  • Tsukasa Aoki,
  • Tsukasa Aoki,
  • Fumitaka Hiura,
  • Aonan Li,
  • Nan Yang,
  • Nana Takakura-Hino,
  • Satoru Mukai,
  • Miho Matsuda,
  • Fusanori Nishimura,
  • Eijiro Jimi,
  • Eijiro Jimi

DOI
https://doi.org/10.3389/fimmu.2023.1179007
Journal volume & issue
Vol. 14

Abstract

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Periodontal disease is an infectious disease that affects many people worldwide. Disease progression destroys the alveolar bone and causes tooth loss. We have previously shown that alymphoplasia (aly/aly) mice harboring a loss-of-function mutation in the map3k14 gene, which is involved in p100 to p52 processing of the alternative NF-κB pathway, exhibited mild osteopetrosis due to decreased number of osteoclasts, suggesting the alternative NF-κB pathway as a potential drug target for the amelioration of bone disease. In the present study, wild-type (WT) and aly/aly mice were subjected to silk ligation to establish a periodontitis model. Alveolar bone resorption was suppressed in aly/aly mice by decreased numbers of osteoclasts in the alveolar bone in comparison to WT mice. Furthermore, the expression of receptor activator of NF-κB ligand (RANKL) and TNFα (cytokines involved in osteoclast induction in periligative gingival tissue) was decreased. When primary osteoblasts (POBs) and bone marrow cells (BMCs) derived from WT and aly/aly mice were prepared and co-cultured, osteoclasts were induced from WT-derived BMCs, regardless of the origin of the POBs, but hardly formed from aly/aly mouse-derived BMCs. Furthermore, the local administration of an NIK inhibitor, Cpd33, inhibited osteoclast formation and thereby inhibited alveolar bone resorption in the periodontitis model. Therefore, the NIK-mediated NF-κB alternative pathway can be a therapeutic target for periodontal disease.

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