Can dental problems be indicative of clonal hematopoiesis?

A new study published in Cell provides evidence that clonal hematopoiesis of indeterminate potential (CHIP) can promote bone loss in periodontal disease and rheumatoid arthritis through pro-inflammatory mechanisms.

Clonal hematopoiesis of indeterminate potential (CHIP) is a condition where hematopoietic cells acquire mutations that allow them to undergo a clonal expansion.¹ Individuals who harbor these mutant clones do not display overt hematological abnormalities; however, they are at increased risk of developing hematological malignancies, cardiovascular disease and other age-related conditions. A new study in Cell has added another item to this growing list of diseases. Wang et al.² report that CHIP is associated with an increased risk of periodontitis, a severe gum infection that can destroy the bone supporting the teeth. This study examined 4946 participants aged 52–74 from the Dental Atherosclerosis Risk in Communities study and found that 3.9% of participants harbored a CHIP mutation using whole-exome sequencing data obtained by conventional next-generation DNA sequencing. Of these, 61.8% carried mutations in the DNMT3A gene, and many individuals with DNMT3A CHIP also suffered from severe periodontitis. To experimentally explore the relationship between DNMT3A mutations and periodontitis, the researchers created chimeric mice with 10% Dnmt3a^R878H mutated bone marrow stem cells (equivalent to the human hotspot mutation DNMT3A^R882H) and 90% normal cells. These mice exhibited an expansion of mutated cells and increased levels of transcripts encoding inflammatory cytokines (Il1b, Il6, and Tnf) in gingival tissue, suggestive of early stages of periodontal disease. When periodontitis was experimentally induced, mice displayed greater inflammation and more severe features of periodontal disease. Further investigation of periodontal tissue revealed that the hematopoietic Dnmt3a^R878H mutation led to increased leukocyte infiltration, elevated levels of inflammatory cytokines, impaired function of regulatory T cells, and enhanced osteoclast differentiation. To extend these observations, Wang et al. also examined a model of rheumatoid arthritis, and found that Dnmt3a^R878H bone marrow transplantation promoted pathological processes through similar mechanisms.

Interestingly, non-mutant cells also produced higher levels of inflammatory cytokines when the system was primed with Dnmt3a^R878H bone marrow,² illustrating the “bystander effect” induced by CHIP that has also been found in other studies.^3,4 Further analysis revealed that Dnmt3a^R878H immune cells displayed widespread DNA hypomethylation and increased gene expression, particularly in the mTOR metabolic network that regulates cell growth, proliferation, and survival.² Treatment with the mTOR inhibitor rapamycin, an FDA-approved drug for organ transplant rejection, mitigated the progression of periodontitis. These findings underscore the potential of targeting the mTOR pathway for managing bone diseases associated with DNMT3A^R882 CHIP, and they further suggest that repurposing existing drugs could offer new therapeutic avenues in treating CHIP-related inflammatory diseases.

The findings discussed above dovetail with a recent study by Kim et al. that examined the effect of CHIP on osteoporosis.⁵ This study examined 113,641 UK Biobank participants and detected CHIP in 5.7% of these individuals. After adjusting for confounding risk factors, individuals harboring CHIP mutations were found to have a 1.44-fold higher risk of developing osteoporosis compared to those without detectable CHIP. The researchers demonstrated causality by showing that chimeric mice with Dnmt3a-deficient hematopoietic cells (equivalent to the non-R882H DNMT3A mutations seen in CHIP patients) had reduced femoral bone density. They further reported that while Dnmt3a-deficient osteoclast precursors displayed similar differentiation potential to wild-type cells, these myeloid cells expressed higher levels of inflammatory cytokines. The study concluded that the bone mass decline mediated by hematopoietic Dnmt3a deficiency is due in part to increased IL-20 expression in myeloid cells, which can non-autonomously enhance the differentiation of osteoclast precursors. These findings suggest that Dnmt3a mutations in mice, both R878H and non-R878H, exacerbate bone resorption via enhanced inflammation, highlighting the need for targeted therapies that address these specific molecular pathways.

The epigenetic impacts induced by the R882H mutation are thought to differ from those caused by the nonsense, non-R882H mutations in DNMT3A.^6,7 Studies have suggested that the DNMT3A^R882H mutation encodes a protein that has a dominant-negative effect on the wild-type DNMT3A protein.^8,9 This difference has been exemplified by data from model systems, where Dnmt3a^R878H mutants may confer a higher self-renewal capability to hematopoietic stem cells (HSCs) compared to non-R8789H mutants in mice.^10,11 In the context of bone disease, it is reported that the R878H mutation accelerates cell-autonomous osteoclastogenesis in bone marrow through RANKL induction in CD11b^–/loLy6C^hi osteoclast progenitors,² whereas the non-R882H mutations enhance osteoclastogenesis through non-cell autonomous mechanisms.⁵ Thus, additional analyses of the differences between R882H and non-R882H mutations are warranted as they may provide further clinical granularity in understanding CHIP-associated diseases in humans.

Periodontitis, osteoporosis, and rheumatoid arthritis share common mechanisms involving chronic inflammation and increased osteoclast activity. Pro-inflammatory cytokines play key roles in stimulating osteoclast activity, leading to bone and tissue damage in all three conditions. In periodontitis, this results in the resorption of alveolar bone and subsequent tooth loss (Fig. 1). In osteoporosis, it causes systemic bone loss and reduced bone density. In rheumatoid arthritis, the immune system’s attack on joint tissues leads to inflammation, cartilage and bone damage, and joint deformities. The recent findings that DNMT3A CHIP dysregulates osteoclastogenesis and enhances inflammation further highlight the interconnectedness of these diseases. Understanding these shared pathways underscores the need for integrated treatment strategies targeting inflammation and osteoclast activity. Additionally, screening for DNMT3A CHIP in patients could enable earlier personalized interventions, potentially mitigating the severe outcomes associated with these conditions.

Fig. 1: DNMT3A CHIP dysregulates bone resorption.

DNMT3A mutant immune cells (pink) in CHIP influence wild-type immune cells (blue) to enhance inflammation. Combined with accelerated osteoclastogenesis, this leads to increased bone resorption, exacerbating conditions such as periodontitis, rheumatoid arthritis, and osteoporosis. Illustrated by Yusuke Hanioka, MD.