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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\u2010CD4\n                    <jats:sup>+<\/jats:sup>\n                    cytotoxic T lymphocyte (CTL) crosstalk. In the osteoblastic niche, SIRT1 promotes the secretion of crucial chemokines, such as C\u2010C motif chemokine ligand 3 (CCL3), C\u2010C motif chemokine ligand 5 (CCL5), and C\u2010X\u2010C motif chemokine ligand 10 (CXCL10), by upregulating dishevelled\u2010associated activator of morphogenesis 2 (DAAM2) through the acetylation of enhancer of zeste homolog 2 (EZH2), activating and recruiting CD4\n                    <jats:sup>+<\/jats:sup>\n                    CTLs that eliminate senescent osteoblasts in a major histocompatibility complex class II (MHC\u2010II)\u2010dependent manner, slowing the bone ageing process and ameliorating osteoporosis. DAAM2 serves as a pivotal downstream effector for SIRT1 to exert immune\u2010regulatory effects in the bone microenvironment; thus, targeting DAAM2 can treat osteoporosis by increasing CD4\n                    <jats:sup>+<\/jats:sup>\n                    CTL responses. These results will facilitate the development of customised therapies targeting senescent osteoblasts to maintain bone health.\n                  <\/jats:p>","DOI":"10.1002\/advs.202501170","type":"journal-article","created":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T13:53:16Z","timestamp":1753537996000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Osteoblast\u2010CD4\n                    <sup>+<\/sup>\n                    CTL Crosstalk Mediated by SIRT1\/DAAM2 Axis Prevents Age\u2010Related Bone Loss"],"prefix":"10.1002","volume":"12","author":[{"given":"Bin","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics Northern Jiangsu People's Hospital Affiliated to Yangzhou University Yangzhou 225001 China"},{"name":"Northern Jiangsu People's Hospital Yangzhou 225001 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to Yangzhou University Yangzhou 225001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanhao","family":"Wei","sequence":"additional","affiliation":[{"name":"The Yangzhou School of Clinical Medicine of Dalian Medical University Yangzhou 225001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Lu","sequence":"additional","affiliation":[{"name":"CUHK\u2010SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences The Chinese University of Hong Kong Hong Kong 999077 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering City University of Hong Kong Hong Kong SAR 999077 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason Pui Yin","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, School of Clinical 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