Objective:

To investigate how STING signaling in bone marrow macrophages contributes to age-related bone loss and whether targeting this pathway improves skeletal outcomes in mice.

Approach:

• Models and methods: Researchers studied genetically modified and wild-type male mice aged 3 to 24 months, using genetic deletion, macrophage-targeted knockdown, pharmacologic treatment, and cellular and molecular assays.
• Outcomes: They assessed bone microarchitecture, bone formation, marrow adipocytes, inflammatory signaling, mitochondrial function, and NAD-positive metabolism.

Key Findings:

• STING signaling in bone marrow macrophages increased with age. Myeloid-specific STING deletion attenuated bone loss from 10 to 24 months, although the bone-mass difference at 24 months was not statistically significant.
• Macrophage-targeted STING knockdown from 12 to 18 months improved several bone microarchitecture measures and was associated with increased bone formation and reduced marrow adipocyte accumulation.
• Combined H-151 and NMN treatment improved bone microarchitecture, increased mineral apposition rates, and reduced inflammatory and senescence-associated markers. Improvements were comparable to those observed with alendronate in this mouse experiment.
• The study identified soluble DPP4 from aging marrow adipocytes as a contributor to STING activation through TLR4. STING-related CD38 activity was associated with inflammation and reduced NMN availability, impairing NAD-positive metabolism and mitochondrial fun…
• Macrophage-targeted CD38 knockdown attenuated bone loss and improved mesenchymal stem-cell mitochondrial function and osteogenic differentiation.

Interpretation:

The authors described bone marrow macrophage STING signaling as an integration hub in age-related deterioration of the marrow microenvironment and skeletal aging.

Limitations:

• Myeloid-specific STING deletion also affected other myeloid cells, including osteoclast precursors, so their contributions could not be excluded.
• The marrow-adipocyte targeting approach could also affect stromal and adipogenic progenitor cells.
• Broad observation intervals and the absence of bone-mass assessments at 1 to 2 months limited evaluation of early skeletal development.
• The combined H-151 and NMN experiment lacked separate treatment groups, preventing assessment of each intervention's individual contribution.
• The findings are from preclinical models; efficacy and safety in humans have not been established.

Conclusion:

The study supports involvement of the STING–CD38 pathway in age-related bone marrow and skeletal deterioration in mice. The authors declared no conflicts of interest.

Sources:

• Advanced Science (study; URL not provided)