Functional disability and pain are the most common symptoms in both OA and RA, which also serve as benchmark of arthritis severity. Similar symptoms impede reliable discrimination of these two diseases[10], especially when the anti-CCP protein are negative[11]. Although the causes of inflammation in the two diseases are different, synovitis promotes their progression. In our study, we downloaded five datasets from multiple synovial samples of advanced OA and RA for analysis.
Although the pathogenesis of RA remains to be determined, a combination of genetic factors and environmental affects the onset of the disease[12]. Among them was Epstein-Barr virus (EBV) infection and patients with RA have impaired control of EBV infection[13]. Based on our result, CCNA2 was an EBV‐related DEG in inflammatory synovial tissue of RA.
CCNA2 (also known as Cyclin A2) is a key protein in the cell cycle, it belongs to family of highly conserved cyclin. The protein, in complex with cyclin-dependent kinase(CDK1 and CDK2), promotes the initiation and is highly expressed from S phase to early mitosis[14]. Research by Kanakkanthara et al. suggested that, CCNA2 is a regulator of various mechanisms of DNA replication, combining multiple kinase dependent functions with kinase independence. RNA binding dependency ensures adequate repair of common replication errors (Kanakkanthara et al., 2016). Studies have confirmed that CCNA2 is blamed to tumorigenesis, but we did not find clear evidence about the correlation between CCNA2 and RA. As a hub gene, CCNA2 was upregulation in synovial tissue of RA according to our study and we speculate that CCNA2 plays a role in RA.
The multidomain protein kinase BUB1B (also known as BubR1) is a core component of the mitotic spindle assembly checkpoint It is an essential self-monitoring system of the eukaryotic cell cycle, which ensures the high fidelity of chromosome segregation by delaying the beginning of anaphase until all chromosomes are correctly oriented in two directions on the spindle of mitosis[15]. BUB1B has been implicated in fundamental biological processes such as cell division, cancer, aging and age-related diseases and studies into the biological relevance have gained the discovery that BUB1B levels markedly decline with aging[16]. Both increased and decreased expression levels of BUB1B have been found to be associated with cancer[17].
In addition to BUB1B, PTTG1 is also a upregulated hub gene enriched in Human T-cell leukemia virus 1 infection pathway. PTTG1 prevents separins from promoting sister chromatid separation, it is highly expressed across a number of tumor types, and has been shown to modulate cancer-related angiogenesis, metastasis, and therapeutic response[18]. The research relieved that BUB1B and PTTG1 levels significantly increase in synovial tissue of advanced RA. We did not retrieve the results about the association between the two genes and RA and our research may provide a new perspective for understanding the mechanism of RA.
In recent years, more and more studies have shown that knee osteoarthritis was a syndrome that affects all joint tissues, including cartilage, subchondral bone, synovium, ligaments, and other soft tissues[19]. The changes of synovial inflammation may have occurred before visible articular cartilage degeneration[20]. Synovial inflammation and the degradation and destruction of articular cartilage induced by synovial-related inflammatory factors promote the development of osteoarthritis. In addition, there is a strong correlation between synovitis and chronic pain. Therefore, inflammatory synovial tissue may be a key target for the treatment of OA.
CHRM5 (also called M5 mAChR, HM5) is a member of G protein-coupled receptors (GPCRs). CHRM5 is usually postsynaptic and increase membrane resistance and therefore input sensitivity[21] and it is widely distributed in the central and peripheral nervous system. In the central nervous system, CHRM5 could be found in the ventral midbrain, primarily in dopaminergic neurons in the VTA and substantia nigra[22], and in the peripheral nervous system, it is in lung, urethral brush cell, bladder and testis[22, 23]. In addition, a certain amount of nonneuronal CHRM5 is located within the endothelium of the cerebral vasculature, it is a mediator of vasodilation in the cerebral vasculature, and thereby, suggesting that the receptor may may have therapeutic relevance for cerebrovascular diseases or acute ischemic stroke[24]. CHRM5 is a potential novel target for pharmacotherapies aimed at treating alcohol use disorders[25] and the receptor could provide an alternative therapeutic approach for reducing the addictive effects of opioids without altering their analgesic properties[22]. Central sensitization and pain accompanied by progression of osteoarthritis and opioids such as oxycodone are often used for postoperative analgesia. CHRM5, as a downregulated DEG, was selected to be an hub gene in PPI network and it was enriched in Neuroactive ligand-receptor interaction according to analysis of KEGG pathway.
GFAP(also known as ALXDRD), which belongs to the family of intermediate filament, has been implicated in cell migration, motility, mitosis and it contributes to the mechanical integrity of cells and is involved in cell signaling[26]. GFAP is considered as a biomarker for astrocytes, the level of GFAP rise with brain injury, astroglial tumors[27] , but the precise function of GFAP is still not fully understood[26]. and central nervous system degeneration(Progress in Neurobiology). In addition to astrocytes and even central nervous system cells, this protein is also found in myoepithelial cells (Hainfellner et al., 2001; Viale et al., 1991) chondrocytes (Hainfellner et al.,2001; Kepes et al., 1984), schwann cells[28] and fibroblasts indicate origin from the neural crest[29]. To date, no convincing evidence of the expression of GFAP in myelinating Schwann cells has been observed, therefore, GFPA can be utilized as a suitable marker for the non-myelinating Schwann cell[30]. GFAP, as a downregulated DEG, was selected to be an hub gene in PPI network and it was enriched in Jak-STAT signaling pathway according to analysis of KEGG pathway. The Jak-STAT signaling pathway plays an important role in the signalling pathway of neuropoietic cytokines[31]. The effects of the JAK/STAT pathway were timedependent in reactive astrocytes, positive and protective in early phases while negative and inhibitory in the later chronic phase[32], which maybe part of the explanation for the decrease in GFAP in our results.
Studies by Pujol et al and Stangl et al suggested that there is a decrease in the density of nerve fibers in the synovium of OA[33, 34] and changes of nerves such as truncated and tangled are likely related to neuropathic pain[35]. Peripheral ectopic impulse generation could originate from multiple sites on axons or in neuromas in dysfunctional nerve fibers. These ectopic leads to abnormal sensations as well as hyperalgesia and allodynia[33]. To date, there have been conflicting opinions regarding the role of neuropathic pain mechanisms in OA, and our results supported the conclusion of a decrease in the density of nerve fibers in the synovium of advanced OA [36]. Our research may deepen the understanding of pain mechanisms and further investigation is needed to explore the question.