■软骨细胞衰老加重OA进展的机制尚未得到很好的阐明。本研究的目的是研究OA中软骨细胞衰老相关基因的生物特征。并分析OA衰老的潜在机制。
■我们基于基因操作实验和基因表达profilin,将来自GEO数据库的骨关节炎数据集GSE82107和来自CellAge数据库的衰老数据集相交,筛选出4个重叠基因。通过qRT-PCR在体外和人OA软骨组织中验证了hub基因。我们通过qRT-PCR进一步证实了促分裂原活化蛋白激酶12(MAPK12)和Fos原癌基因(FOS)在体外和体内OA中的功能,西方印迹,Edu染色,免疫荧光,SA-β-gal染色,他,IHC,VonFrey测试,和热板。
■从GSE82107中确定了1458个下调和218个上调的DEG,并从CellAge数据库中下载了279个人类衰老相关基因。交叉分析后,我们筛选出4个重叠的基因,其中FOS,CYR61和TNFSF15上调,MAPK12下调。MAPK12的表达明显下调,而FOS的表达谱,CYR61和TNFSF15在H2O2-或IL-1β刺激的C28/I2细胞中显著上调,人OA软骨组织,和衰老小鼠的膝盖软骨。此外,MAPK12过表达和FOS敲低均能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H2O2-或IL-1β刺激的C28/I2细胞和小鼠原代软骨细胞的关节痛,内侧半月板(DMM)小鼠的去稳定。
■本研究探讨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,并提供了一些证据作为随后可能的OA治疗靶点。
■本文的翻译潜力是,我们发现MAPK12和FOS可以通过调节软骨细胞衰老来有效缓解OA,从而为将来预防或治疗OA提供了潜在的治疗靶点。
UNASSIGNED: 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.
UNASSIGNED: 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 in vitro 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 in vitro and in vivo by qRT-PCR, western blotting, Edu staining, immunofluorescence, SA-β-gal staining, HE, IHC, von frey test, and hot plate.
UNASSIGNED: 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 H2O2- 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 H2O2- or IL-1β-stimulated C28/I2 cells and mouse primary chondrocytes, destabilization of the medial meniscus (DMM) mice.
UNASSIGNED: 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.
UNASSIGNED: 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.