Osteoblast‐CD4 ⁺ CTL Crosstalk Mediated by SIRT1/DAAM2 Axis Prevents Age‐Related Bone Loss

The dynamic production and clearance of senescent osteoblasts affects bone homeostasis and health. However, the relationship between senescent osteoblasts and the immune system remains unclear. Here, a landscape of the interaction between immune cells and osteoblasts through spatial analysis of the bone microenvironment is presented. Sirtuin 1 (SIRT1), a longevity gene, regulates bone mass maintenance through a mechanism involving osteoblast-CD4⁺ cytotoxic T lymphocyte (CTL) crosstalk. In the osteoblastic niche, SIRT1 promotes the secretion of crucial chemokines, such as C-C motif chemokine ligand 3 (CCL3), C-C motif chemokine ligand 5 (CCL5), and C-X-C motif chemokine ligand 10 (CXCL10), by upregulating dishevelled-associated activator of morphogenesis 2 (DAAM2) through the acetylation of enhancer of zeste homolog 2 (EZH2), activating and recruiting CD4⁺ CTLs that eliminate senescent osteoblasts in a major histocompatibility complex class II (MHC-II)-dependent manner, slowing the bone ageing process and ameliorating osteoporosis. DAAM2 serves as a pivotal downstream effector for SIRT1 to exert immune-regulatory effects in the bone microenvironment; thus, targeting DAAM2 can treat osteoporosis by increasing CD4⁺ CTL responses. These results will facilitate the development of customised therapies targeting senescent osteoblasts to maintain bone health.