Chen Bolin, Zhu Runjiu, Hu Hao, Zhan Mingbin, Wang Tingxuan, Huang Fangli, Wei Fuxin, Chai Yu, Ling Zemin, Zou Xuenong
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Front Cell Dev Biol. 2022 Jul 8;10:853688. doi: 10.3389/fcell.2022.853688. eCollection 2022.
Senolytics are a class of drugs that selectively eliminate senescent cells and ameliorate senescence-associated disease. Studies have demonstrated the accumulation of senescent disc cells and the production of senescence-associated secretory phenotype decrease the number of functional cells in degenerative tissue. It has been determined that clearance of senescent cell by senolytics rejuvenates various cell types in several human organs, including the largest avascular structure, intervertebral disc (IVD). The microvasculature in the marrow space of bony endplate (BEP) are the structural foundation of nutrient exchange in the IVD, but to date, the anti-senescence effects of senolytics on senescent vascular endothelial cells in the endplate subchondral vasculature remains unclear. In this study, the relationships between endothelial cellular senescence in the marrow space of the BEP and IVD degeneration were investigated using the aged mice model. Immunofluorescence staining was used to evaluate the protein expression of P16, P21, and EMCN in vascular endothelial cells. Senescence-associated β-galactosidase staining was used to investigate the senescence of vascular endothelial cells. Meanwhile, the effects of senolytics on cellular senescence of human umbilical vein endothelial cells were investigated using a cell culture model. Preliminary results showed that senolytics alleviate endothelial cellular senescence in the marrow space of BEP as evidenced by reduced senescence-associated secretory phenotype. In the aged mice model, we found decreased height of IVD accompanied by vertebral bone mass loss and obvious changes to the endplate subchondral vasculature, which may lead to the decrease in nutrition transport into IVD. These findings may provide evidence that senolytics can eliminate the senescent cells and facilitate microvascular formation in the marrow space of the BEP. Targeting senescent cellular clearance mechanism to increase nutrient supply to the avascular disc suggests a potential treatment value of senolytics for IVD degenerative diseases.
衰老细胞裂解剂是一类能选择性清除衰老细胞并改善衰老相关疾病的药物。研究表明，衰老椎间盘细胞的积累以及衰老相关分泌表型的产生会减少退变组织中功能细胞的数量。现已确定，衰老细胞裂解剂清除衰老细胞可使包括最大的无血管结构——椎间盘（IVD）在内的多个人体器官中的多种细胞类型恢复活力。骨终板（BEP）骨髓腔中的微血管是IVD营养物质交换的结构基础，但迄今为止，衰老细胞裂解剂对终板软骨下脉管系统中衰老血管内皮细胞的抗衰老作用仍不清楚。在本研究中，使用老年小鼠模型研究了BEP骨髓腔中内皮细胞衰老与IVD退变之间的关系。采用免疫荧光染色评估血管内皮细胞中P16、P21和EMCN的蛋白表达。使用衰老相关β-半乳糖苷酶染色研究血管内皮细胞的衰老情况。同时，使用细胞培养模型研究衰老细胞裂解剂对人脐静脉内皮细胞衰老的影响。初步结果表明，衰老细胞裂解剂可减轻BEP骨髓腔中的内皮细胞衰老，衰老相关分泌表型减少即为证据。在老年小鼠模型中，我们发现IVD高度降低，伴有椎体骨量丢失以及终板软骨下脉管系统明显改变，这可能导致营养物质向IVD的运输减少。这些发现可能提供证据表明，衰老细胞裂解剂可清除衰老细胞并促进BEP骨髓腔中的微血管形成。针对衰老细胞清除机制以增加对无血管椎间盘的营养供应，提示衰老细胞裂解剂对IVD退行性疾病具有潜在的治疗价值。
