Deletion of p16 accelerates fracture healing in geriatric mice.

The biomarker p16 plays a role in aging and is upregulated in aged organs and cells, including bone marrow mesenchymal stem cells (BM-MSCs), which play a leading role in fracture healing. Several studies have reported delayed fracture healing in geriatric mice. However, the relationship between p16 expression and fracture healing in geriatric mice remains poorly understood. In this study, we found that fracture healing was accelerated in p16 deletion (p16) mice, and the number of migrated BM-MSCs from p16 mice increased. The expressions of SDF-1 and CXCR4 were also upregulated in p16 mice. Increased cell percentage at S phase in cell cycle, enhanced expressions of CDK4/6, pRB, and E2F1, decreased expression of RB, and elevated expressions of SOX9, PCNA, and COL2A1 were detected in p16 mice. The expressions of COL10A1, MMP13, OSTERIX, and COL1A1 were also high in p16 mice. Moreover, the expressions of p-AKT, p-mTOR, HIF-1α, and VEGF-A in BM-MSCs and expression of VEGF-A in callus were upregulated in p16 mice. The expression of VEGF in the serum of p16 mice was also higher than that of wild type mice. Thus, deletion of p16 enhances migration, division, and differentiation of BM-MSCs, promotes proliferation and maturation of chondrocytes, activates osteoblastogenesis, and facilitates vascularization to accelerate fracture healing, providing a novel strategy to treat fracture in the elderly.