Chk2 deletion rescues Bmi1 deficiency-induced mandibular osteoporosis by blocking DNA damage response pathway

Bmi1 deficiency has been proved to be able to cause mandibular osteoporosis through suppressing oxidative stress. However, the role of DNA damage response pathway in this pathogenesis had not been well understood. In this study, we investigate whether mandibular osteoporosis induced by Bmi1 deficiency could be rescued by blocked DNA damage response pathway.

The protein expression levels of antioxidant enzymes and DNA damage and damage response pathway molecules in mandibular tissue were examined using Western blots. Double knockout mice that lacked both Bmi1 and Chk2 were generated and their mandibular phenotypes were compared at 6 weeks old to wild-type, Chk2^-/-, and Bmi1^-/- mice using radiograph, micro-CT, histopathology, cellular and molecular techniques.

Bmi1 deficiency induces oxidative stress and DNA damage and activates DNA damage response pathways in mouse mandibles. Chk2 deletion rescued mandibular osteoporosis through promoting formation of osteoblastic bone as well as decreasing osteoclastic bone resorption. Mechanistically, Chk2 deletion suppressed oxidative stress, DNA damage, as well as cell senescence. In addition, it boosted proliferation of bone marrow mesenchymal stem cells (BM-MSCs) that derived from mandible through blocking the DNA damage response pathway.

Abolish the expression of Chk2 could rescue Bmi1 deficiency-related mandibular osteoporosis through promoting BM-MSC proliferation and osteoblastic bone formation, reducing osteoclastic bone resorption, decreasing oxidative stress, inhibiting damage of DNA and associated response pathways, suppressing cell senescence as well as senescence-associated secretory phenotype (SASP). These findings offer a theoretical basis for using Chk2 or p53 inhibitors to prevent and treat age-related mandibular osteoporosis.