Bone aging does not begin with senescent cells alone: osteocytes show a transitional state

One-year-old mice have a larger proportion of osteocytes associated with bone resorption

In an August 13 preprint reporting a mouse study, the authors compared males at 12 and 52 weeks. The one-year-old animals had an expanded population of osteocytes that expressed inflammatory genes and RANKL, a protein that helps osteoclast precursors mature.

Bone is constantly renewed. Osteoblasts build new tissue, while osteoclasts break down old material. Osteocytes, long-lived cells embedded within bone, send signals to both cell types.

The authors created a mouse line in which an administered toxin primarily eliminates osteocytes. Earlier genetic tools also affected osteoblasts. They compared males aged 10 weeks and one year. Eliminating osteocytes increased bone mass at both ages. In the young animals, osteoblast activity increased. In the one-year-old animals, the number and activity of osteoclasts decreased.

To investigate the basis of this difference, the researchers mapped gene activity using RNA from individual bone cells collected from mice at 12 and 52 weeks. Young animals were dominated by osteocytes with a program for producing extracellular matrix, the material between cells. In the one-year-old animals, a state that the authors called transitional became more common. Cells in this state produced RANKL more frequently and activated inflammatory genes.

The transitional population overlapped only partially with cells showing signs of senescence, a state in which cells stop dividing and alter their activity. The one-year-old mice received dasatinib and quercetin once a month for four months. The drugs had little effect on bone mass or bone remodeling and did not reproduce the effect of eliminating osteocytes.

Genetic cell elimination demonstrated an age-related change in bone remodeling. The RNA map showed a change in cellular programs. The drug experiment showed that the senolytic regimen used in the study did not produce the same result. In this mouse model, the transitional osteocyte state overlaps only partially with senescence.