Spatial analysis of the bone microenvironment reveals a novel osteoblast-CD4+ CTL crosstalk mediated by the SIRT1/DAAM2 axis

Abstract During ageing, the dynamic balance between the production and clearance of senescent osteoblasts affects bone homeostasis and health. However, the relationship between senescent osteoblasts and the immune system remains unclear. Here, we provide evidence that SIRT1, known as a longevity gene, could orchestrate bone mass maintenance through a novel mechanism involving osteoblast- CD4+ cytotoxic T lymphocyte (CTL) crosstalk. In the osteoblastic niche, SIRT1 promotes the secretion of key chemokines (e.g. CCL3, CCL5, and CXCL10) by upregulating DAAM2 through acetylation of EZH2 protein, thereby activating and recruiting CD4+ CTLs. Then, CD4+ CTLs eliminate senescent osteoblasts in an MHC-II-dependent manner, slowing the bone ageing process and effectively alleviating osteoporosis. This mechanism shows that DAAM2 is a pivotal downstream effector for SIRT1 to exert immune-regulatory effects in the bone microenvironment, and that targeting DAAM2 could accurately treat osteoporosis by increasing CD4+ CTL responses. This work enables a multi-perspective assessment of physiological bone senescence, paving the way for customised therapies targeting senescent osteoblasts to maintain bone health.