P21/P16 Senescence Heterogeneity In Diabetic Bone

Aim or purpose: To investigate bone compartment-specific senescence heterogeneity in type 2 diabetic mice, focusing on spatiotemporal p16/p21 expression patterns and differential efficacy of senolytic therapies. Materials and methods: Longitudinal profiling (1-6 weeks post-diabetes induction) of femoral cortical and marrow tissues in p21-3MR transgenic mice (n=6/group) integrated the following approaches: (1) Senescence flux analysis: Senescence-Associated β-galactosidase and senescence-associated secretory phenotype factor arrays; (2) Molecular cartography: p16/p21 co-localization via mRFP-IF; (3) Targeted interventions: dasatinib and quercetin (D+Q) therapy vs ganciclovir nanotherapy.All experimental protocols were approved by the Animal Ethics Committee. Results: (1) Spatiotemporal divergence in diabetic bone aging was observed: bone marrow exhibited early-onset p21-related senescence, whereas cortical bone demonstrated progressive p16-related pathology.(2) Therapeutic efficacy mapping revealed compartment-specific responses:D+Q therapy showed superior cortical bone rejuvenation (P<0.01), whereas p21-targeted monotherapy preferentially attenuated marrow senescence (p21high cell reduction: 73% vs 15% in cortex, P<0.001).(3) This compartmentalized senescence paradigm establishes dual therapeutic targets for diabetic osteopathy, proposing bone structure-specific intervention strategies to address aging heterogeneity. Conclusions: This pioneering study employing the p21-3MR model unveils spatiotemporal heterogeneity in diabetic bone-adipose axis senescence and delineates compartment-specific therapeutic efficacy of anti-aging interventions. The findings establish a novel therapeutic paradigm: cortical bone preferentially responds to D+Q, whereas marrow senescence requires p21-targeted strategies. Future investigations should prioritize mechanistic decoding of p21high adipocyte populations in metabolic dysregulation, to advance personalized senotherapy for diabetic osteopathy.