Numerous studies have demonstrated that a substantial portion of individuals afflicted with SARS-CoV-2 infection manifest a spectrum of symptoms subsequent to the acute phase, encompassing fatigue, dyspnea, and sleep disturbances. This prolonged aftermath is termed "long-term COVID," and over 200 symptoms impacting various organ systems have been identified. This scenario presents a significant challenge to public health and societal well-being 16. Hyperactivated natural immunity and "cytokine storms" have been suggested as potential pathogenic mechanisms for COVID-19 11. While coronavirus infection is primarily linked to respiratory symptoms, it has also been acknowledged that risks and complications associated with the skeletal system exist 17,18. Many COVID-19 patients display disruptions in bone metabolism, such as hypocalcemia and vitamin D deficiency 19,20. OA constitutes a degenerative joint ailment characterized by pathological changes encompassing articular cartilage degradation, synovial capsule thickening, subchondral bone sclerosis, and bony outgrowths. The processes of inflammation and immune response are pivotal contributors to osteoarthritis progression. Consequently, an intricate relationship between COVID-19 infection and the onset and advancement of OA is conceivable 21–23.
This study encompassed a series of bioinformatics analyses. The COVID-19 dataset (GSE180226 and GSE171110) and the OA dataset (GSE55235 and GSE1919) were acquired from the GEO database. Subsequently, we conducted separate differential analysis in the COVID-19 and OA datasets. Following this, we derived common DEGs through the intersection of these two DEG sets. Subsequently, the Cytoscape plugin CytoHubba was employed to rank common DEGs based on their MCC scores. From this analysis, we identified the top nine genes with the highest scores, designating them as hub genes. These hub genes were subsequently validated using independent databases and simple experiments. The findings suggested potential close associations between COL1A1, COL1A2, MMP9, THBS1, SERPINE1, and MMP1 with both OA and COVID-19. Studies have demonstrated that heightened secretion of type I collagen, encoded by COL1A1 and COL1A2 homotrimers in OA, leads to subchondral bone stenosis and disorganized collagen fibers 24. While type I collagen is uncommon in normal chondrocytes, elevated levels have been identified in osteoarthritic cartilage, particularly in advanced stages of the condition 25. Additionally, type I collagen serves as a crucial structural protein in the lungs, and its production is triggered during specific inflammatory responses. Research indicates that patients with adult respiratory distress syndrome exhibit heightened requirements for type I collagen 26. MMP-1, primarily synthesized by synoviocytes within joints, functions as a collagenase responsible for the degradation of all extracellular matrix components. Furthermore, MMP-9 expression experiences elevation in osteoarthritis, primarily contributing to the degradation of non-collagenous matrix components within the joint. 27. The expression of both MMP-1 and MMP-9 significantly influences the progression of pulmonary fibrosis and plays a significant role in predicting the prognosis of patients infected with COVID-19 28. THBS1 functions as a mediator orchestrating cell adhesion dynamics induced by stress and injury, alongside its role in the production of extracellular matrix proteins 29. The SERPINE1 protein constitutes a pivotal member of the E superfamily of serine protease inhibitors, which exert a critical role within the fibrinolytic system. It has been recognized to have links with chronic inflammatory lung conditions like allergic asthma and pulmonary fibrosis 30.
To gain insights into the shared disease mechanisms between COVID-19 and OA, we performed GO and KEGG analyses on the common DEGs. The identified common DEGs exhibited notable enrichment in pathways including the regulation of leukocyte activation, MHC class II protein complex, extracellular matrix, and IL-17 signaling pathway. The outcomes of the aforementioned enrichment analysis indicate the potential significance of immune and inflammatory responses in the context of both OA and COVID-19. Research has demonstrated that severe COVID-19 cases manifest severe lymphopenia, robust T-cell activation, and heightened expression of T-cell suppressor molecules 31. Disruption in the regulation of leukocyte activation ultimately triggers irregular immune cell activation, cytokine storms, and systemic inflammatory responses. These cascading effects exacerbate clinical symptoms in COVID-19 patients and may even culminate in multi-organ failure. Chondrocytes possess receptors for extracellular matrix (ECM) components. In the context of osteoarthritis, the inflammatory response induces modifications in extracellular matrix constituents, resulting in the degradation of articular cartilage structure and function 32. The inflammatory response elicited by SARS-CoV-2 viral infection has the potential to induce remodeling and deterioration of the extracellular matrix within lung tissue 33. In instances of severe COVID-19, lung fibrosis may manifest, with alterations in the extracellular matrix being a pivotal contributor. Deviations in the processes of extracellular matrix synthesis and degradation may precipitate lung fibrosis and subsequent tissue scarring. The enrichment analysis conducted for these pathways has augmented our comprehension of the underlying mechanisms in OA patients afflicted with COVID-19.
We investigated the interplay between Transcription Factors (TFs), microRNAs (miRNAs), and common DEGs. TFs are proteins that selectively bind to DNA sequences, governing transcription and gene expression 14. These molecules are pivotal in numerous biological processes, including gene transcription, metabolic control, and immune modulation, by targeting specific gene sequences. MiRNAs are petite noncoding RNAs with the capacity to repress target gene expression by binding to complementary sites within the 3' untranslated region of post-transcribed mRNAs 13. MiRNAs govern target gene regulation across diverse biological processes, potentially encompassing genes with roles in cancer promotion or tumor suppression. The leading 10 TFs, ranked based on their corresponding P values, consist of SMAD3, JUN, EP300, SMAD4, VDR, CEBPA, FOS, GTF3C2, NFE2L2, and TBP. The miRNAs positioned within the top 10 based on their respective P values encompass hsa-miR-29b-3p, hsa-miR-29a-3p, mmu-let-7e-5p, hsa-miR-145-5p, hsa-miR-6825-5p, hsa-miR-30c-5p, mmu-miR-320-3p, hsa-miR-29c-3p, hsa-miR-4689, and hsa-miR-30d-5p. SMAD3, a pivotal intracellular messenger of the transforming growth factor-β (TGF-β) signaling pathway, holds significance as a growth factor for maintaining the integrity of articular cartilage 34. Within the nucleus, the SMAD3-SMAD4 complex engages in interactions with other transcription factors and co-regulatory elements to oversee the expression of distinct genes. FOS proteins establish dimeric complexes by binding with JUN proteins, thereby participating in a diverse array of biological processes such as cell proliferation, differentiation, apoptosis, inflammatory response, and stress response 35. EP300 assumes significance in the context of cell proliferation and differentiation 36. VDR predominantly participates in regulating calcium and phosphorus metabolism to uphold bone health, while also engaging in diverse physiological processes including immune modulation, cell division, and inflammatory response 37. NFE2L2 is a pivotal transcription factor contributing significantly to the oxidative stress response via activation of the NFE2L2/NRF2 pathway. This pathway curtails the release of pro-inflammatory cytokines in response to human coronavirus SARS-CoV-2 infection and virus-derived ligands. Additionally, it impedes SARS-CoV-2 replication through a mechanism independent of type I interferon (IFN) 38. The impact of additional TFs on the interplay between COVID-19 and OA warrants further investigation. Of all miRNAs, hsa-miR-29b-3p appears to wield a potent regulatory influence on the advancement of OA 39. The miRNAs hsa-miR-29a,b,c-3p might be intricately linked to the pathogenic process of SARS-CoV-2 infection via engagement with the IL-6/STAT3 pathway 40. Research has demonstrated a potential close correlation between hsa-miR-145-5p and the growth of airway smooth muscle cells, which could potentially influence the prognosis of patients with COVID-19 41. Further exploration is warranted to understand the effects of additional miRNAs on both COVID-19 and OA contexts.
Additionally, a genetic disease analysis was conducted to discern diseases linked with the common DEGs. The findings reveal that the common DEGs implicated in both OA and COVID-19 are correlated with a range of diseases, encompassing Glioblastoma, Liver carcinoma, Degenerative polyarthritis, Endometriosis, Rheumatoid Arthritis, Neoplasm Metastasis, Ehlers-Danlos syndrome type 1,Liver Cirrhosis, Acute lymphocytic leukemia, and Pulmonary Fibrosis. Studies propose that SARS-CoV-2 could potentially inflict harm upon the liver, particularly in cases of decompensated cirrhosis, warranting its consideration as a risk factor for severe COVID-19 and associated mortality 42. Furthermore, COVID-19 exhibits a pronounced correlation with a variety of tumors, which is consistent with our results above. Patients diagnosed with cancer face an elevated susceptibility to severe COVID-19 disease and consequent mortality due to the disease's severity and the compromised state of their immune system resulting from the ailment 43. Diseases like degenerative polyarthritis, rheumatoid arthritis, and osteoarthritis exert their impact on the joints, with certain molecular genetic associations observed across varying forms of arthritis 44. Pulmonary fibrosis stands out as a prominent complication stemming from COVID-19. Despite the survival of numerous COVID-19 patients through the acute phase of the disease, a substantial portion succumbs to progressive pulmonary fibrosis 45. The FDA has sanctioned antiviral medications, like Paxlovid, for COVID-19 treatment. Nevertheless, it's imperative to acknowledge potential side effects of these drugs on chondrocytes 6. Presently, no research demonstrates the efficacy of any particular therapeutic agent in ameliorating clinical outcomes among COVID-19-infected OA patients or halting disease progression. This underscores the necessity to develop a secure and efficacious drug to address COVID-19-infected OA cases. Presently, no research demonstrates the efficacy of any particular therapeutic agent in ameliorating clinical outcomes among COVID-19-infected OA patients or halting disease progression. Therefore, there is an urgent need to develop a safe and effective drug tailored to treat patients with both COVID-19 and OA. In the context of this study, we identified a diverse range of compounds and drugs that exhibit potential usefulness in addressing both COVID-19 and OA. These include progesterone, genistein, estradiol, dexamethasone, trichostatin A, Retinoic acid, Decitabine, Bisphenol A, ZINC, and cytarabine. Certain investigations indicate that female reproductive steroids, specifically estrogens and progesterone, alongside their derivatives, exhibit anti-inflammatory properties, modulate immune cell functionality, enhance antibody production, and facilitate restoration and renewal of epithelial cell of the respiratory tract. This indicates potential utility in mitigating COVID-19 symptoms 46. Dexamethasone exerts formidable and sustained anti-inflammatory as well as immunosuppressive influences, potentially leading to diminished COVID-19 mortality rates 47. Additional research suggests that dexamethasone could additionally impede disease advancement in the context of osteoarthritis 48. Trichostatin A exhibits the capacity to impede osteoarthritis by suppressing MMP-1, MMP-3, MMP-13, and IL-1 gene expression 49. Administering a retinoic acid metabolism blocker (RAMBA) conduces to diminishing cartilage damage and inflammation via a peroxisome proliferator-activated receptor γ (PPARγ)-dependent pathway 50. SARS-CoV2 infection potentially triggers a reduction in Retinoic acid reserves. This resultant deficiency in Retinoic acid induced by infection could potentially hinder the lung's capability to restore impaired epithelial surfaces, conceivably contributing to pulmonary fibrosis and subsequent lung capacity reduction 51. Zinc ions serve to inhibit coronavirus RNA polymerase activity, effectively thwarting virus replication 52. A meta-analysis unveiled that zinc supplementation substantially impacted the reduction of mortality in COVID-19 patients 53. These drugs hold potential for application in treating patients afflicted with both COVID-19 and OA.