美国宾夕法尼亚大学George Hajishengallis团队发现，由突变的DNMT3A驱动的克隆造血促进炎症性骨质流失。2024年6月4日，《细胞》杂志在线发表了这项成果。
在4946名居住在社区的成年人中，研究人员发现具有不确定潜能的克隆性造血（CHIP）-DNMT3A突变与牙周炎和牙龈炎症的高发病率有关。为了建立DNMT3A驱动的CHIP模型，研究人员使用了杂合功能缺失突变R878H（相当于人类热点突变R882H）的小鼠。用Dnmt3aR878H/+骨髓（BM）细胞进行部分移植会导致突变细胞克隆扩增到髓系和淋巴系，并导致BM中破骨细胞前体和外周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，并加重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驱动的克隆性造血以及随后的牙周炎。DNMT3A驱动的CHIP代表了一种可治疗的促进炎性骨质流失的适应不良造血状态。
研究人员表示，CHIP是由造血祖细胞中与衰老相关的获得性突变引起的，它表现出克隆性扩增并产生表型改变的白细胞。
附：英文原文
Title: Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss
Author: Hui Wang, Kimon Divaris, Bohu Pan, Xiaofei Li, Jong-Hyung Lim, Gundappa Saha, Marko Barovic, Danai Giannakou, Jonathan M. Korostoff, Yu Bing, Souvik Sen, Kevin Moss, Di Wu, James D. Beck, Christie M. Ballantyne, Pradeep Natarajan, Kari E. North, Mihai G. Netea, Triantafyllos Chavakis, George Hajishengallis
Issue&Volume: 2024-06-04
Abstract: 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 Dnmt3aR878H/+ 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.
DOI: 10.1016/j.cell.2024.05.003
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00492-6