Geng Nana, Xian Menglin, Deng Lin, Kuang Biao, Pan Yiming, Liu Kaiwen, Ye Yuanlan, Fan Mengtian, Bai Zhixun, Guo Fengjin
State Key Laboratory of Ultrasound in Medicine and Engineering, School of Basic Medical Sciences, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
Department of Orthopaedic Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
J Orthop Translat. 2024 Jun 20;47:50-62. doi: 10.1016/j.jot.2024.06.008. eCollection 2024 Jul.
The mechanism by which chondrocyte senescence aggravate OA progression has not yet been well elucidated. The aim of this study was to investigate the chondrocyte senescence related gene biosignatures in OA, and to analyze on the underlying mechanisms of senescence in OA.
We intersected osteoarthritis dataset GSE82107 from GEO database and senescence dataset from CellAge database of human senescence-associated genes based on genetic manipulations experiments plus gene expression profilin, and screened out 4 overlapping genes. The hub genes were verified and in human OA cartilage tissues by qRT-PCR. We further confirmed the function of mitogen-activated protein kinase 12 (MAPK12) and Fos proto-oncogene (FOS) in OA and by qRT-PCR, western blotting, Edu staining, immunofluorescence, SA-β-gal staining, HE, IHC, von frey test, and hot plate.
1458 downregulated and 218 upregulated DEGs were determined from GSE82107, and 279 human senescence-associated genes were downloaded from CellAge database. After intersection assay, we screened out 4 overlapping genes, of which FOS, CYR61 and TNFSF15 were upregulated, MAPK12 was downregulated. The expression of MAPK12 was obviously downregulated, whereas the expression profiles of FOS, CYR61 and TNFSF15 were remarkedly upregulated in HO- or IL-1β-stimulated C28/I2 cells, human OA cartilage tissues, and knee cartilage of aging mice. Furthermore, both MAPK12 over-expression and FOS knock-down can promote cell proliferation and cartilage anabolism, inhibit cell senescence and cartilage catabolism, relieve joint pain in HO- or IL-1β-stimulated C28/I2 cells and mouse primary chondrocytes, destabilization of the medial meniscus (DMM) mice.
This study explored that MAPK12 and FOS are involved in the occurrence and development of OA through modulating chondrocyte senescence. They might be biomarkers of OA chondrocyte senescence, and provides some evidence as subsequent possible therapeutic targets for OA.
The translation potential of this article is that we revealed MAPK12 and FOS can effectively alleviate OA by regulating chondrocyte senescence, and thus provided potential therapeutic targets for prevention or treatment of OA in the future.
软骨细胞衰老加剧骨关节炎（OA）进展的机制尚未完全阐明。本研究旨在探究OA中与软骨细胞衰老相关的基因生物标志物，并分析OA中衰老的潜在机制。
我们基于基因操作实验和基因表达谱，将来自基因表达综合数据库（GEO）的骨关节炎数据集GSE82107与来自人类衰老相关基因的CellAge数据库的衰老数据集进行交叉分析，筛选出4个重叠基因。通过qRT-PCR在人OA软骨组织中验证了枢纽基因。我们通过qRT-PCR、蛋白质免疫印迹法、Edu染色、免疫荧光、SA-β-半乳糖苷酶染色、苏木精-伊红（HE）染色、免疫组化（IHC）、von Frey试验和热板法进一步证实了丝裂原活化蛋白激酶12（MAPK12）和原癌基因Fos（FOS）在OA中的作用。
从GSE82107中确定了1458个下调和218个上调的差异表达基因（DEG），并从CellAge数据库下载了279个人类衰老相关基因。经过交叉分析，我们筛选出4个重叠基因，其中FOS、CYR61和肿瘤坏死因子配体超家族成员15（TNFSF15）上调，MAPK12下调。在过氧化氢（HO）或白细胞介素-1β（IL-1β）刺激的C28/I2细胞、人OA软骨组织和衰老小鼠的膝关节软骨中，MAPK12的表达明显下调，而FOS、CYR61和TNFSF15的表达谱明显上调。此外，MAPK12过表达和FOS敲低均可促进细胞增殖和软骨合成代谢，抑制细胞衰老和软骨分解代谢，减轻HO或IL-1β刺激的C28/I2细胞和小鼠原代软骨细胞、内侧半月板不稳定（DMM）小鼠的关节疼痛。
本研究探讨了MAPK12和FOS通过调节软骨细胞衰老参与OA的发生发展。它们可能是OA软骨细胞衰老的生物标志物，并为后续OA可能的治疗靶点提供了一些证据。
本文的转化潜力在于我们揭示了MAPK12和FOS可通过调节软骨细胞衰老有效减轻OA，从而为未来预防或治疗OA提供了潜在的治疗靶点。
