STING Signaling in Bone Marrow Macrophages Links Senescent Adipocytes to NAD+ Depletion and Osteogenic Decline
STING in marrow macrophages integrates signals from senescent adipocytes via DPP4, depletes NAD+, and drives age-related bone loss in mice. The pathway shows opposing effects at young versus old ages. Evidence remains preclinical and requires human validation plus safety assessment of chronic inhibition.
Researchers crossed STING-floxed mice with LysM-Cre lines to delete the pathway specifically in bone marrow macrophages. Young knockouts exhibited lower bone mineral density, yet aged knockouts preserved trabecular volume and showed reduced inflammatory cytokine expression compared with wild-type littermates. Co-culture experiments isolated DPP4 secretion from old adipocytes as the upstream trigger that activated STING and lowered NAD+ in neighboring stromal cells, blocking their differentiation into osteoblasts.
VITALIS: A 12-month trial of a DPP4 inhibitor in adults over 65 will report at least 4% lumbar spine BMD gain versus placebo if baseline marrow fat fraction exceeds 40%.
Sources (2)
- [1]Primary Source(https://doi.org/10.1002/advs.77571)
- [2]Supporting Source(https://www.nature.com/articles/s41574-022-00715-0)