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

## TL;DR

This study shows how SIRT1 and DAAM2 help CD4+ T cells remove old bone cells, preventing age-related bone loss and osteoporosis.

## Contribution

The study identifies a novel SIRT1/DAAM2 axis that mediates immune-cell clearance of senescent osteoblasts.

## Key findings

- SIRT1 upregulates DAAM2 to promote chemokine secretion, recruiting CD4+ CTLs to the bone niche.
- CD4+ CTLs eliminate senescent osteoblasts via MHC-II-dependent mechanisms, slowing bone aging.
- Targeting DAAM2 could offer a new therapeutic strategy for osteoporosis.

## Abstract

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.

In the osteoblastic niche, SIRT1 activates and recruits CD4+ CTLs by increasing DAAM2 expression via EZH2 deacetylation and boosting the secretion of key chemokines, such as CCL3, CCL5, and CXCL10. Then, CD4+ CTL directly eliminates senescent osteoblasts in an MHC‐II‐dependent way, thereby slowing down the process of bone ageing and effectively alleviating osteoporosis.