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

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.