In a new study, researchers from the National Institute of Dental Craniofacial Research (NIDCR) have found that blocking the function of a coagulation protein prevents bone loss caused by periodontal (gingival) disease in mice. According to animal and human data, they found that the accumulation of this clotting protein called fibrin triggers an excessive immune response that damages the gingiva and underlying bones. They point out that inhibition of abnormal fibrin activity may hold promise for the prevention or treatment of periodontal disease, as well as other inflammatory diseases marked by fibrin accumulation, including arthritis and multiple sclerosis. The findings were published in Science, entitled “Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier”.
Nearly half of the United States over the age of 30 suffers from periodontal disease, and 70% of people over the age of 65 suffer from periodontal disease. It is caused by bacteria infecting a tissue that supports the teeth. In the early stages, periodontal disease causes redness and swelling (inflammation) of the gums. In advanced stages, that is, periodontitis, the underlying bone is damaged, resulting in tooth loss. Although scientists have known that periodontitis is partially driven by an excessive immune cell response, until now, it is unclear what triggers this response and how it causes tissue and bone damage.
Dr. Rena D’Souza, director of the NIDCR, said, “Severe periodontal disease may lead to tooth loss. For many Americans, especially those who lack adequate dental care, the disease remains a barrier to productivity and quality of life. By providing the most comprehensive description of the underlying mechanisms of periodontal disease to date, this study brings us closer to developing more effective preventive and therapeutic approaches.”
At sites of injury or inflammation, fibrin often plays a protective role, helping to form blood clots and activate immune cells to fight infection. However, excessive fibrin is associated with health problems, including a rare form of periodontitis, caused by plasminogen (PLG) deficiency. In affected people, mutations in the PLG gene lead to fibrin accumulation and disease in various parts of the body including the mouth.
To explore the link between abnormal fibrin accumulation and periodontitis, researchers led by NIDCR researchers Dr. Niki Moutsopoulos and Dr. Thomas Bugge studied PLG defects in mice and analyzed human genetic data.
Like humans with this disease, PLG-deficient mice develop periodontitis, including periodontal bone loss and elevated fibrin levels in the gingiva. The gingiva of mice is crowded with immune cells called neutrophils, which are also found in high amounts in common periodontitis.
Neutrophils usually protect the oral cavity from harmful microorganisms. However, excessive neutrophil response is thought to cause tissue damage.
To find out whether fibrin is driving this excessive response, these authors disrupted its ability to interact (bind) with protein receptors on the neutrophil surface. After the binding between fibrin and neutrophils was disrupted, periodontal bone loss was completely prevented in PLG-deficient mice. Alarmingly, it also reduced bone loss in normal mice with a common, age-related form of periodontitis, suggesting that similar mechanisms are at work in both forms of the disease.
“This study shows that fibrin can lead to a shift in neutrophil immune response from protective to destructive in some cases,” says Moutsopoulos. “This fibrin-neutrophil binding may be a driver of periodontitis.”
Genetic analysis of more than 1,000 seems to support these findings in mice. Even in the absence of PLG deficiency, mutations in the PLG gene are associated with an increased risk of severe periodontitis, consistent with the idea that similar processes lead to rare and common forms of periodontitis.
In summary, this study shows that excessive accumulation of fibrin in the gingiva — whether due to genetic changes such as PLG, chronic inflammation caused by bacterial infections, or a combination of the two—triggers an increase in neutrophil response, ultimately leading to periodontal disease.
These results are also consistent with the findings of other research teams that found that elevated fibrin may lead to other inflammatory diseases and autoimmune diseases, such as arthritis and multiple sclerosis, and that interfering with fibrin activity may help treat these diseases.
Lead author Dr. Lakmali Silva added, “Our data support the idea that targeting fibrin-neutrophil interactions may be a promising therapeutic approach to explore rare and common periodontitis.”