Exacerbation of inflammatory bone loss in TET2-driven clonal hematopoiesis.

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) arises from age-related somatic mutations in hematopoietic stem cells in the bone marrow (BM), driving clonal expansion and altered phenotypes. Loss-of-function mutations in the epigenetic regulator TET2 are among the most frequent in CHIP and increase the risk of hematologic malignancies and chronic inflammatory disorders. Here, we investigated the impact of TET2-driven CHIP on inflammatory bone loss. Partial BM reconstitution with TET2-deficient (Tet2-/-) cells promoted clonal expansion and spontaneous periodontitis, characterized by gingival inflammation and alveolar bone loss. Furthermore, mice with TET2-driven CHIP exhibited heightened susceptibility to experimentally induced bone loss, including ligature-induced periodontitis and collagen antibody-induced arthritis. This inflammatory bone loss phenotype was associated with increased tissue infiltration of hyperinflammatory Tet2-/- neutrophils and monocytes, elevated IL-17-producing CD4⁺ T cells (Th17), and enhanced osteoclastogenesis driven by paracrine signals from Tet2-/- myeloid cells acting on wild-type osteoclast precursors. Although T cell-intrinsic TET2 deficiency minimally affected Th17 differentiation in vitro, Tet2-/- dendritic cells exhibited enhanced capacity to drive Th17 differentiation from wild-type CD4⁺ T cells. These findings reveal mechanistic links between TET2-driven CHIP and the pathogenesis of inflammatory bone loss disorders.