Bone Marrow Macrophage STING Signaling is a Direct Nexus Linking Marrow Adipose Expansion to NAD

Zhichao Li, Kuanhui Gao, Mengjie Wang, Songlin Liang, Dandan Li, Guoqing Tan, Haipeng Xue, Yujie Liu, Peng Zhang, Zhanwang Xu, Wenxiang Cheng, Yongjun Wang, Nianhu Li

Center For Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.Center For Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. · pubmed

Paper

Abstract

Reversing the destructive remodeling of the bone marrow microenvironment during aging remains a major challenge. Here, we reveal an age-dependent dual role of bone marrow macrophage (BMM) STING signaling during skeletal aging. While BMM STING deficiency is detrimental during early bone development and maturation, it paradoxically confers protection against age-related bone loss from middle age onward. Mechanistically, accumulating bone marrow adipocytes secrete substantial soluble dipeptidyl peptidase 4 (sDPP4). This sDPP4 functions as an extracellular ligand for Toll-like receptor 4 on BMMs, thereby collaborating with endogenous mitochondrial DNA to activate STING signaling. This STING activation concurrently induces a CD38-dependent salvage synthesis pathway. Importantly, this STING-driven upregulation of CD38 not only amplifies bone marrow inflammation but also, through its ecto-nicotinamide adenine dinucleotide (NAD

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Research summary

The paper claims that inhibiting STING signaling in bone marrow macrophages prevents age-related bone loss by blocking a CD38-dependent NAD depletion pathway triggered by marrow adipose expansion. This is relevant because it identifies a specific molecular mechanism (STING-CD38-NAD axis) driving the deterioration of the bone marrow microenvironment during aging, offering a potential target for reversing skeletal aging rather than just treating osteoporosis symptoms.

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