Han Yongli, Qiao Wanxin, Xue Qi, Miao Dengshun, Dong Zhan
Department of Nursing, Changzhou Hygiene Vocational Technology College, Changzhou 213000, China.
The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Stem Cells. 2025 Mar 10;43(3). doi: 10.1093/stmcls/sxae088.
Premature osteoporosis caused by parathyroid hormone-related peptide (PTHrP) dysfunction presents significant bone health challenges. The role of p16-mediated cellular senescence in this condition remains unclear.
Using a Pthrp knock-in (KI) mouse model lacking the nuclear localization sequence and C-terminus of PTHrP, we generated p16⁻⁄⁻KI mice and compared them with wild-type, p16⁻⁄⁻, and KI mice. We analyzed survival, skeletal phenotypes, bone marrow mesenchymal stem cell (BM-MSC) function, and molecular markers of senescence.
Genetic ablation of p16 in KI mice extended their lifespan, increased body size and weight, and improved skeletal growth. Micro-CT analysis revealed significantly increased bone volume, while histological studies showed enhanced chondrocyte proliferation and osteoblast function in p16⁻⁄⁻KI mice compared to KI mice. In vitro experiments demonstrated enhanced differentiation capacity and reduced senescence of BM-MSCs from p16⁻⁄⁻KI mice, as evidenced by increased colony formation and osteogenic marker expression. Molecular analyses indicated that p16 knockout partially reversed oxidative stress, DNA damage, and cellular senescence observed in KI mice, shown by upregulated antioxidant enzymes, reduced DNA damage markers, and decreased senescence markers.
p16-mediated cellular senescence plays a crucial role in premature osteoporosis caused by PTHrP dysfunction. Targeting cellular senescence pathways may offer a promising therapeutic strategy for treating premature osteoporosis and age-related bone loss.
由甲状旁腺激素相关肽（PTHrP）功能障碍引起的过早骨质疏松对骨骼健康构成重大挑战。p16介导的细胞衰老在这种情况下的作用仍不清楚。
利用缺乏PTHrP核定位序列和C末端的Pthrp基因敲入（KI）小鼠模型，我们培育出p16⁻⁄⁻KI小鼠，并将它们与野生型、p16⁻⁄⁻和KI小鼠进行比较。我们分析了生存率、骨骼表型、骨髓间充质干细胞（BM-MSC）功能以及衰老的分子标志物。
KI小鼠中p16的基因缺失延长了它们的寿命，增加了体型和体重，并改善了骨骼生长。显微CT分析显示骨体积显著增加，而组织学研究表明，与KI小鼠相比，p16⁻⁄⁻KI小鼠的软骨细胞增殖和成骨细胞功能增强。体外实验表明，p16⁻⁄⁻KI小鼠的BM-MSC分化能力增强且衰老减少，集落形成增加和成骨标志物表达增加证明了这一点。分子分析表明，p16基因敲除部分逆转了KI小鼠中观察到的氧化应激、DNA损伤和细胞衰老，表现为抗氧化酶上调、DNA损伤标志物减少和衰老标志物降低。
p16介导的细胞衰老在PTHrP功能障碍引起的过早骨质疏松中起关键作用。靶向细胞衰老途径可能为治疗过早骨质疏松和年龄相关骨质流失提供一种有前景的治疗策略。
