The talin1-p53 axis inhibits osteocyte senescence to promote bone mass and mediate skeletal adaptation to mechanical stimulation.

Background

Osteoporosis is a major public health concern worldwide. As the predominant and long-lived bone cells, osteocytes serve as key regulators of bone remodeling and mechanotransduction. However, the molecular mechanisms underlying their regulatory roles remain poorly understood. The roles of talin1, a key focal adhesion protein linking integrins to the cytoskeleton, in regulation of osteocyte function and skeletal homeostasis remain unclear.

Methods

Osteocyte-specific talin1 conditional knockout (cKO) mice were established, and their skeletal phenotypes were assessed through micro-CT, histomorphometry, and biomechanical analyses. Osteocyte senescence and molecular signaling were assessed by RNA sequencing analysis, immunostaining, and biochemical assays. Talin1-p53 interactions were characterized by co-immunoprecipitation and pull-down assay. Rescue experiments were performed using talin1 and p53 double KO mice.

Results

Talin1 expression in osteocytes was markedly reduced during skeletal aging in mice and humans. Osteocyte-specific deletion of talin1 disrupted FA integrity and dendritic networks, leading to severe osteopenia in weight-bearing bones and impaired bone mechanical properties. Talin1 deficiency altered the bone marrow microenvironment, suppressing osteoblast differentiation while enhancing adipogenesis. Mechanistically, talin1 bound and sequestered p53 in the cytoplasm for proteasomal degradation. Thus, talin1 loss enhanced p53 nucleotranslocation, inducing upregulation of p16 and p21 and osteocyte senescence. Importantly, genetic ablation of p53 in osteocytes rescued the low bone mass phenotype, defective bone formation, and excessive senescence caused by talin1 loss.

Conclusions

This study identifies talin1 as a key factor governing osteocyte senescence and bone mass. We define a novel talin1-p53 axis that links impaired focal adhesion signaling to osteocyte senescence and bone loss, highlighting potential therapeutic targets for aging-related osteoporosis.