Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3a^R878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.

不确定潜能克隆造血 (CHIP) 是由造血祖细胞中与衰老相关的获得性突变引起的，这些突变表现出克隆扩张并产生表型改变的白细胞。我们将 CHIP-DNMT3A 突变与 4,946 名社区居住成年人中较高的牙周炎和牙龈炎症患病率联系起来。为了模拟 DNMT3A 驱动的 CHIP，我们使用了具有杂合功能丧失突变 R878H（相当于人类热点突变 R882H）的小鼠。 Dnmt3a ^R878H/+ 骨髓 (BM) 细胞的部分移植导致突变细胞克隆扩增到骨髓和淋巴谱系，并且 BM 中破骨细胞前体和周围破骨细胞巨噬细胞的丰度升高。受体小鼠中 DNMT3A 驱动的克隆造血促进了自然发生的牙周炎，并加剧了实验诱导的牙周炎和关节炎，这与破骨细胞生成增强、IL-17 依赖性炎症和中性粒细胞反应以及调节性 T 细胞免疫抑制活性受损有关。雷帕霉素治疗抑制了 DNMT3A 驱动的克隆造血和随后的牙周炎。 DNMT3A 驱动的 CHIP 代表了一种可治疗的适应不良造血促进炎症性骨质流失的状态。