Recently, with an increase of aging populations and chronic conditions, both OA and RA become the most common causes of musculoskeletal-related chronic joint disorders in elders [28, 29]. There were many common methods for the diagnosis and treatment of OA and RA. However, the clinical outcomes were still not satisfactory . Genomic studies had recently been widely used to enhance the diagnosis and treatment of many diseases . As a result, a large number of fragmented research and analysis had been done to obtain genomic information related to OA and RA. To further investigate the genomic profiles of OA and RA, we systematically analyzed these multiple microarray data sets using an integrated method with the biggest sample sizes so far.
A total of 1723 OA-specific DEGs, including 1690 up- and 33 down-regulated were screened, respectively. Ubiquitin was significantly enriched in OA-related GO terms and pathways of DEGs. PPI network highlighted some genes such as RPS6 and RPS14. Among that, 1683 overlapping genes were obtained, and 71 DEGs were acquired such as TPM2, NCAM2, MFHAS1 after eliminating RA-related genes. The study found 1460 RA-specific DEGs in total (1278 up- and 182 down-regulated DEGs). Some genes were identified through PPI networks such as CTNNB1 and SNRPA1. A total of 40 RA-specific genes were acquired such as CUX1, KANK1, MBTPS2 after calculation. These DEGs may be of important meaning for the occurrence and progression of OA and RA.
Autophagy was related to cellular homeostasis mechanism and responsible for metabolic regulation, largely via the removal and regression of biologically damaged intracellular products, which were in consequence of improving cartilage aging and development of structural changes [31, 32]. The recent finding supported that autophagy response machineries were regulated by some genes, such as the mammalian target of rapamycin (mTOR). Mammalian TORC-1 was adjusted by PI3K/Akt signaling pathways, as well as further regulated multiple protein synthesis and modification by phosphorylating ribosomal S6 protein kinase (RPS6) [33, 34]. RPS6 participated in the mTOR signal pathway as well as dependent growth program and was triggered by anabolic signals . There was evidence suggested that expression of mTOR increased in OA joint cartilage , thus, genetic or pharmaceutical inhibition of mTOR signaling pathway can lead to autophagy activation and further protection from OA [36, 37].
Recent study data suggested that the multi aspects contribution of the sphingolipid machinery concerning osteoclast-osteoblast crosstalk represented one of the significant interactions underlying bone and cartilage homeostasis . Under this situation, imbalances in the interrelated between osteoblasts and osteoclasts might cause bone-related illnesses such as osteoporosis, Paget’s disease, RA, and bone metastases [39, 40]. Quint P found that activation of both S1PR1 and S1PR2 can synergistically stimulate the migration of osteoblast precursors . Far more telling was that the expression of S1PR2 preserved sensitivity to S1P at the preosteoblast process as well as osteoblast stage . Broadly speaking, the recent data showed that the expression of S1PR2 was a pivotal gene for the progression of osteoblasts to S1P ensuring the scenario under which the osteoblast precursors were conserved in the marrow during osteoblastogenesis .
Fibroblast-like synoviocytes (FLSs) participated in the pathogenesis and occurrence of RA. Experiments demonstrated that MALAT1 was decreased expressed in the FLSs of RA illness. The current study revealed that MALAT1 reduced the secretion of multiple inflammatory cytokines, while its purpose was to promote the apoptosis of FLSs in RA  A previous report suggested that MALAT1 could promote the methylation on the CTNNB1 promoter region and consequently inhibit CTNNB1, resulting in the inactivation of the Wnt signaling pathway . Li et al. found that the CTNNB1 promoter methylation and Wnt pathway inactivation inhibited the secretion of MALAT1-related inflammatory cytokine production of FLSs such as IL-1β, TNF-α, IL-6, and IL-8 in RA . Together with the above studies, the understanding of the MALAT1-CTNNB1-Wnt pathway in the progression of RA may be of benefit to the understanding of cellular and molecular mechanisms of RA, with underlying of acting as a target point for treatments of RA.
Previous studies suggested that the biological process of ubiquitination and the proteasome led to OA by regulating the expression of inflammatory cytokines, such as MMP13 . Frank et al.  found that ubiquitin was an integral part of ubiquitin-like proteins, which covered the Small Ubiquitin-related Modifiers (SUMO). Through the histological analysis of synovial tissue obtained from OA and RA patients, SUMO had definitely been related to MMP13 expression level. In the meantime, via the NF-κB pathway, SUMO-2/3 was differentially controlled by TNF-α and selectively regulated corresponding MMP expression .
Jia et al. suggested that the EGFR signaling pathway was needed for acquiring an adequate number of joint superficial chondrocytes via regulating proliferation ability, improving survival, and keeping superficial properties . Previous work by the same institution found that EGFR signaling pathway played a pivotal role in growth plate development and secondary ossification center formation through building a chondrocyte-specific EDFR knockout mouse model [50, 51]. Sun et al.  put forward a concept of heterogeneous OA subgroup, especially, the pEGFRhigh expression OA subgroup. The research pointed out that the character of EGFR in deeply exploring OA made EGFR a promising hot topic of therapy. Findings from the Daneshmand study also suggested that modulation of the EGFR pathway can promote mesochondrium synthesis and suppress OA cartilage degradation .
Genome-Wide Association Studies (GWAS) had identified hundreds of associations of autoimmune disorders. Utilizing this data, Lee et al. detected FOXO3 activity as the severity of rheumatoid arthritis, acting via the modulation of cytokine production in monocytes. In the meantime, a Foxo3a haplotype was related to erosion scores in adult RA as the previous report. Some reports said that in RA joint synovial tissue, modulation of known transcriptional FoxO-related factors played a role in FoxO proteins of integrating inflammatory stimuli to regulate cell survival and apoptosis . Besides, inhibition of both PI3K/AKT and MEK/ERK signaling pathways induced FOXO transcriptional activity, and the result was significantly inhibited cell migration as well as capillary tube formation . What’s more, angiogenesis was the pathological characteristic of the RA synovial membrane .
Three PPI networks of multigroup DEGs were established using STRING and overlapped connected-nodes were constructed to further acquire the deep relationship of OA and RA. Moreover, we validated the top 10 genes by performing ROC analysis with the testing latest dataset GSE153015. As a result, all 10 genes with p value < 0.05 as well as AUC > 0.50 showed satisfactory diagnostic value for the pooled data. Then, 10 of distinguished hub genes including RPS6, RPS14, RPS25, RPL11, RPL27, SNRPE, EEF2, RPS29 and RPL10A were conducted for experimental verification. After OA and RA model establishment, 30 mice were sacrificed and synovial in bilateral knees were acquired. Further qPCR was performed to study the accuracy of the top 10 genes, and as a result, except RPS29 and RPL10A, other 8 genes were showed consistency with this bioinformatic analysis. Finally, our team chose 30 mice to further verify the veracity of the top 10 hub PPI genes.
Our study also had many limitations that needed to be improved. First, this bioinformatics analysis conducted by synovial tissues may not represent the best way for differential diagnosis of OA and RA. Second, despite collecting maximal samples to the best of our ability, the GEO database in this study was the only approach to acquire related data and perform this data mining. Thus, a multicenter, larger-scale clinical survey was an indispensable thing for further research. In this study, multiple similar genes and signaling pathways were detected to synergistically regulate in both OA and RA. The connection between these genes offered us new evidence for the next research and help us to discover potential biomarkers.