Expression Of Cell Senescence Marker Claudin1 In Human And Mouse Tissues And Organs And Its Role In Mouse Osteoarthritis Model

Among the many factors that cause individual aging,the accumulation of senescent cells is considered to be an important reason that leads to organ aging and degeneration,and finally causes the age-related diseases.Senescent cells undergo changes in cell morphology,transcriptional profiles,protein homeostasis,epigenome and metabolism,and secrete a variety of inflammatory factors called senescence-associated secretory phenotype(SASP).SASP can promote the development of inflammation and aging-related diseases.Moreover,senescent cells resist apoptosis and therefore accumulate in multiple organs and tissues in the body during organisamal aging process.Previously,our laboratory found that the tight junction protein Claudin1(CLDN1)was highly expressed in senescent cells and participates in the resistance of senescent cells to apoptosis,but the tissue specificity of its expression,its significance in disease models and mechanisms remain unclear.Therefore,we focus on these scientific issues for further research and discussion in this paper.First,we used a method of X-ray irradiation to induce a cell senescence model,and verified the specific high expression of CLDN1 in senescent cells in vitro.Then,we further found that CLDN1 was highly expressed in skin and adipose tissue samples of aged mice and humans,suggesting that the high expression of CLDN1 had the characteristics of senescent tissue.Furthermore,destabilisation of medial meniscus(DMM)was used to create an osteoarthritis model in mice.We found that the expression of CLDN1 in articular cartilage was significantly increased in the surgical group.After silencing CLDN1 by injection of adenovirus into the articular cavity,the senescent chondrocytes in the surgery group were partially cleared and the chondrogenic ability was improved.In addition,we used the method of transplanting senescent cells into the articular cavity to induce OA-like changes in mice,and found that silencing CLDN1 can also clear the transplanted senescent cells and improve mouse behavior.In terms of molecular mechanism,we have initially found that over-expressing CLDN1 in IMR90 can inhibit the activation of Caspase8,Caspase9 and Caspase3 against apoptosis induced by TNFa and etoposide stimulation,suggesting that CLDN1 in senescence cells can help them survive by inhibiting the apoptotic signaling pathway.In summary,our research suggests that CLDN1 may be a specific marker of aging skin and adipose tissue in humans and mice,and can be an effective target to clear senescent cells and improve osteoarthritis phenotype in mice,showing a promising application in the treatment of some age-related diseases.