DEL‐1 is an Endogenous Senolytic Protein that Inhibits Senescence‐Associated Bone Loss

Abstract Accumulation of senescent cells in the bone microenvironment, including bone marrow mesenchymal stromal cells (BM‐MSCs), contributes to aging‐related bone degeneration. Developmental endothelial locus‐1 (DEL‐1), the expression of which declines with old age is herein described as an endogenous secreted senolytic protein. DEL‐1 promotes apoptosis of senescent BM‐MSCs via a β3 integrin/CD73/adenosine/p38 mitogen‐activated protein kinase (p38 MAPK)/B‐cell lymphoma‐2 (BCL‐2) pathway, thereby leading to their clearance by macrophages. DEL‐1‐deficiency displays increased abundance of β3 integrin‐rich CD73 + senescent BM‐MSCs and higher chemotherapy‐induced or aging‐related senescence‐associated bone loss. Conversely, mice with endothelial‐specific overexpression of DEL‐1 (EC‐Del1) have decreased numbers of senescent BM‐MSCs and diminish senescence‐associated bone loss. CD73‐deficiency reverses the reduction in senescent BM‐MSC numbers in EC‐Del1 mice. Administration of DEL‐1 (or a DEL‐1‐inducing macrolide) causes a reduction in senescence markers and reverses aging‐related periodontitis. Therefore, DEL‐1 may be harnessed as an endogenous senolytic to prevent senescent cell buildup and senescence‐associated bone loss.