Bone marrow fat in mice triggers an immune signal that depletes the resources cells need to form bone

Bone marrow fat in mice triggers an immune signal that depletes the resources cells need to form bone

On October 15, a paper published in Advanced Science described how bone marrow fat cells alter macrophage function. In male mice, this pathway depleted NAD+ in the stem cells that give rise to bone-forming cells; treatment with H-151 and NMN improved measures of bone structure and density.

Fat cells accumulate in bone marrow with age. At the same time, mesenchymal stem cells, the precursors of bone-forming cells, become less effective at producing bone tissue. The authors tested whether signaling between different bone marrow cells connects these changes.

This pathway involves STING, an innate immune protein activated when DNA appears in the wrong part of a cell. Its role in mice varied with age: young animals lacking Sting had poorer measures of bone structure and density, whereas disabling the gene in macrophages in aging animals slowed bone loss. When STING was suppressed in macrophages from 12 to 18 months of age, bone mineral density and trabecular bone volume fraction at the end of the experiment were higher than in control mice.

The authors identified another step in the pathway in aging bone marrow fat cells. These cells released DPP4, a protein that bound to TLR4, a receptor protein on the macrophage surface. DNA from mitochondria, the energy-producing structures within cells, provided an additional signal. Together, DPP4 and mitochondrial DNA activated STING.

Activated STING increased production of CD38, an enzyme on the macrophage surface. CD38 breaks down extracellular NMN, which neighboring stem cells use to replenish the NAD+ they need for metabolism. In stem cells cultured with old macrophages, NAD+ levels and mitochondrial function declined, and the stem cells became less able to differentiate into bone-forming cells.

In the final set of experiments, the authors treated 12-month-old male mice with a combination of the STING inhibitor H-151 and NMN. By 18 months, these mice had higher bone mineral density and trabecular bone volume fraction, more trabeculae, and less space between them than mice given saline. These findings linked the accumulation of bone marrow fat with age to a reduced capacity to form bone through STING signaling in macrophages and NAD+ depletion in stem cells.