Chk2 deletion rescues bone loss and cellular senescence induced by Bmi1 deficiency via regulation of Cyp1a1.

Background/objective: Bone homeostasis, maintained by a balance between osteoblastic bone formation and osteoclastic bone resorption, is disrupted in osteoporosis, leading to reduced bone mass and increased fracture risk. Bmi1, a polycomb group protein, is crucial for stem cell self-renewal and senescence regulation. Bmi1 deficiency has been linked to oxidative stress, DNA damage, and premature osteoporosis. Checkpoint kinase 2 (Chk2) is a key mediator of the DNA damage response (DDR) pathway, which can exacerbate bone aging through oxidative stress and senescence. This study investigated the role of Chk2 deletion in mitigating bone loss and cellular senescence caused by Bmi1 deficiency and explored the underlying molecular mechanisms, focusing on the regulation of oxidative stress via Cyp1a1. Methods: We utilized Bmi1-deficient (Bmi1 Results: Bmi1 deficiency activated the ATM-Chk2-p53 DDR pathway, increased oxidative stress, and induced osteocyte senescence and senescence-associated secretory phenotype (SASP), leading to reduced osteoblastic bone formation, increased osteoclastic bone resorption, and significant bone loss. Chk2 knockout rescued these defects by reducing oxidative stress and senescence. In Bmi1 Conclusion: Chk2 knockout rescues bone loss and cellular senescence induced by Bmi1 deficiency by reducing oxidative stress through downregulation of Cyp1a1. These findings provide novel insights into the molecular mechanisms underlying bone aging and identify Chk2 and Cyp1a1 as potential therapeutic targets for osteoporosis and age-related bone disorders. The translational potential of this article: This study identifies Chk2 and Cyp1a1 as potential therapeutic targets for osteoporosis and age-related bone loss. Targeting Chk2 or Cyp1a1 could mitigate oxidative stress and cellular senescence, offering a novel approach to preserving bone mass and preventing fractures in aging populations.