An international research group involving the Institute of Clinical Chemistry and Laboratory Medicine (IKL) at the Dresden University Medical Center has published a scientific paper in the renowned journal "Cell". In a broad-based study, the connection between clonal hematopoiesis and diseases with inflammatory bone loss (such as periodontitis and arthritis) was investigated.

In the course of ageing, mutations can occur in blood stem cells. The resulting abnormal growth of these cells is referred to as clonal hematopoiesis of undetermined potential (CHIP). This phenomenon, which has not yet been declared a disease, affects more than ten percent of people over the age of 65. In the study, the scientists investigated the connection between mutations in the DNMT3A gene, a gene most frequently affected by CHIP, and the prevalence and severity of periodontitis. The role of the mutated DNMT3A gene in gingivitis and arthritis was also deciphered.

As people age, the immature progenitor cells, also known as hematopoietic stem cells, from which all blood and immune cells develop, can change. Some of these mutations cause these stem cells to grow more effectively than non-mutated stem cells. "This previously little-studied condition, known as clonal hematopoiesis of undetermined potential (CHIP), carries an increased risk of various inflammation-related diseases," explains Prof. Triantafyllos Chavakis, co-lead author of the study and director of the ICL.

The international team led by Prof. George Hajishengallis from the University of Pennsylvania, together with scientists from the Faculty of Medicine at TUD Dresden University of Technology and the University of North Carolina at Chapel Hill (UNC), has now provided scientific insight into the mechanisms of increased inflammation caused by CHIP. The research team was able to demonstrate a link between DNMT3A, the gene most frequently mutated in CHIP, and the prevalence and severity of periodontitis. They were also able to show that the drug rapamycin, which is used to prevent organ transplant rejection, has the potential to block mutated stem cells and effectively treat inflammatory bone diseases caused by CHIP.

In a cohort of 4,946 people aged between 52 and 74 years and in experimental models, the study demonstrated a strong causal relationship between the occurrence of DNMT3A mutations and an increased susceptibility to inflammatory bone diseases. Model experiments showed that the DNMT3A mutation led to an increase in cells that break down bone tissue. In addition, there was increased inflammation triggered by the cytokine IL-17, higher inflammatory activity of neutrophil granulocytes and impaired function of regulatory T cells, which normally keep the immune response in check. The presence of the CHIP-DNMT3A mutation also led to an overactive mTOR (Mechanistic Targeting of Rapamycin) signaling pathway in hematopoietic stem and progenitor cells, which regulates cell growth and survival. This overactivation causes the mutated clones to proliferate and thus contributes to an increased inflammatory reaction. In this context, the efficacy of the mTOR inhibitor rapamycin in protecting against the inflammatory bone loss exacerbated by CHIP was also demonstrated.

Screening for CHIP in the elderly population could therefore identify individuals at increased risk of concomitant inflammatory diseases. These individuals could then benefit from therapeutic interventions aimed at preventing the abnormal expansion of CHIP-mutated hematopoietic stem cell clones and their negative impact on chronic inflammatory comorbidities.

Open AccessPublished: June 04, 2024 DOI: https://doi.org/10.1016/j.cell.2024.05.003

https://www.cell.com/cell/fulltext/S0092-8674(24)00492-6

contact
University Hospital Carl Gustav Carus Dresden
and Medical Faculty of the TU Dresden
Institute for Clinical Chemistry and Laboratory Medicine
Prof. Dr. Triantafyllos Chavakis, Director
Phone: +49 351 458 2109
E-Mail: Triantafyllos