Immune System and Teeth – How NF-kB Activation Affects Bone Loss in Periodontitis

Picture credit: Biorender

Teeth serve many functions in our daily lives; eating, talking, and communicating emotions through smiling. This dental practice advertisement sums up their aesthetic importance in our lives perfectly:

Without a doubt, maintaining oral hygiene is as important (if not more) as bodily hygiene. Diseases of the gums can not only take away that beautiful smile but also create a lot of other major and long-term issues. One such gum disease, periodontal disease, is the result of infection and inflammation around the gums and bones that support the teeth. As bacterial plaque remains on the teeth for long periods the pathogens can invade and lead to infiltration of immune cells leading to widespread inflammation in this area. This disease can eventually lead to the destruction of the bones supporting the teeth and tooth loss.

There are some cells present on bones called osteoclasts that are involved with alveolar bone resorption or bone degradation. The lipopolysaccharide (LPS) produced by pathogens and inflammatory cytokines from our immune cells lead to the differentiation of hematopoietic stem cells into osteoclasts, via nuclear factor kB (NF-kB) and mitogen-activated protein kinase (MAPK) mediated pathways. NF-kB can be activated through two different pathways: the classical and the alternative. The classical is activated shortly after stimulation by pro-inflammatory cytokines, while the alternative is activated hours later after stimulation by cytokines like CD40L. Mice that have a mutation leading to a loss of function in proteins involved in the NF-kB alternative pathway exhibit a complete lack of osteoclasts, called osteopetrosis. Aoki and colleagues wanted to investigate if a compound, Cpd 33, can be used to target the alternative pathway of NF-kB to treat periodontal disease in such mice. 

To establish the periodontitis mice model the researchers tied a piece of silk around the teeth of the mice on one side, leaving the other side untouched. This silk string will induce tooth and gum issues that are similar to periodontitis. I can’t imagine tying a string around my teeth let alone the teeth of little mice! They used mice (aly/aly) that had a mutation that does not allow for the proper activation of the NF-kB alternative pathway. When looking at the aly/aly mice vs. the wild type (WT) mice, it was clear that the aly/aly mice had fewer osteoclasts and a lower degree of bone resorption than the WT. This indicated a mild bone loss in the mutated mice and now the researchers wanted to dig deeper into the mechanism of the bone loss.

The measurement of an osteoclast differentiation factor, receptor activator of NF-kB ligand (RANKL), and two cytokines that can lead to the generation of osteoclasts showed that all three were reduced in the mutant mice, which makes sense based on what we just saw with the number of osteoclasts. (Make sure to check out the paper itself for some cool pics of the mouse teeth!) It was determined that the differences between the aly/aly and the WT mice were specifically due to the lack of differentiation of cells into osteoclasts when they took hematopoietic cells from the different mice and attempted to differentiate them in the lab. 

Remember the compound Cpd33 that we mentioned earlier? Well, that is a known suppressor of RANKL-induced generation of osteoclasts! The researchers found that the expression of RANKL was suppressed in cells that were stimulated with LPS in vitro. I bet you are wondering, how does this translate to the actual mouse? Excitingly, the injection of Cpd33 led to a significant decrease in bone resorption on the ligated side of the mice’s mouths. With this experimental evidence, we now know that RANKL is an effective target for inhibiting bone resorption in periodontitis. 

This study is just the first step toward using these therapies for people. It is critical to understand the detailed mechanisms for periodontal disease and other related dental problems to find the correct targets for medication. Hopefully, this study will lead to better and more effective therapies for periodontitis so that fewer people will have to be in pain and we can all keep smiling. 

Source:

Aoki T, Hiura F, Li A, Yang N, Takakura-Hino N, Mukai S, Matsuda M, Nishimura F, Jimi E. Inhibition of non-canonical NF-κB signaling suppresses periodontal inflammation and bone loss. Front. Immunol., 18 April 2023 Volume 14 – 2023 https://doi.org/10.3389/fimmu.2023.1179007

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