Inhibition of non-canonical NF-κB signaling suppresses periodontal inflammation and bone loss.
Inhibition of non-canonical NF-κB signaling suppresses periodontal inflammation and bone loss.
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DOI：
10.3389/fimmu.2023.1179007
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
牙周病是一种影响全世界许多人的传染病。疾病进展会破坏牙槽骨并导致牙齿脱落。我们之前已经表明，患有map3k14基因（参与替代NF-κB通路的p100到p52加工）的功能缺失突变的发育不全（aly/aly）小鼠，由于破骨细胞数量减少而表现出轻度骨硬化症，这表明替代NF-κB通路作为改善骨疾病的潜在药物靶点。本研究采用丝线结扎法对野生型（WT）和aly/aly小鼠建立牙周炎模型。与 WT 小鼠相比，aly/aly 小鼠牙槽骨吸收因牙槽骨中破骨细胞数量减少而受到抑制。此外，NF-κB 配体受体激活剂 (RANKL) 和 TNFα（参与洁牙周围牙龈组织破骨细胞诱导的细胞因子）的表达降低。当制备来自WT和aly/aly小鼠的原代成骨细胞(POB)和骨髓细胞(BMC)并共培养时，无论POB的来源如何，破骨细胞均由WT来源的BMC诱导，但几乎不由aly/aly小鼠来源的BMC形成。此外，局部给予NIK抑制剂Cpd33可抑制破骨细胞形成，从而抑制牙周炎模型中的牙槽骨吸收。因此，NIK介导的NF-κB旁路途径可以成为牙周病的治疗靶点。
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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