Rheumatoid arthritis (RA) is a prevalent autoimmune condition that involves chronic joint inflammation and subsequent deterioration of cartilage and bone. Although current antirheumatic treatments utilizing biological agents effectively inhibit proinflammatory cytokines, their frequent administration and potential for systemic immune suppression pose challenges. Consequently, gene transfer strategies are being investigated as a promising alternative for targeted, efficient, and long-lasting delivery of inhibitors for inflammatory cytokines and other therapeutic substances. This approach aims to improve the effectiveness and specificity of RA treatment18.
Recent studies have highlighted the potential of human skin fibroblast cells as a promising therapeutic tool for tissue repair and inflammation suppression in various diseases19. Through genetic manipulation in laboratory settings, modifications can be made to enhance the effectiveness of these cells as a therapeutic approach. AIA model is commonly utilized in preclinical studies. This model is favored for its short experimental duration, ease of measurement, and resemblance to RA. As a result, it has been frequently employed to evaluate the effectiveness of therapeutic agents20. Therefore, in the present study, using the transfection method in genetic engineering, more efficient skin fibroblast cells were created with increased expression of miR-192 and collagen, and these cells were used together with PRP in the treatment of the experimental model of RA disease. In this study, the researchers employed the transfection method in genetic engineering to create highly efficient skin fibroblast cells that exhibited enhanced expression of miR-192 and collagen. These modified cells were then utilized in conjunction with PRP for the treatment of an experimental model of RA disease. The objective was to assess the therapeutic potential of this combined approach.
Overall, the outcomes of this study showed that the use of combined treatment of PRP and HDF cells expressing miR-192 is effective in improving the symptoms of rheumatoid arthritis in the experimental model.
In HDF cells that were engineered to express miR-192, there was a marked increment in the expression of collagen type 1 compared to the control group. This finding aligns with previous research by Fang et al., who demonstrated that SIP1, a cytoplasmic protein, inhibits the phosphorylation of Smad2/3 in the TGF-β/Smad2-3 signaling pathway in renal fibrosis. This inhibition prevents the transfer of Smad to the nucleus and it’s binding to the collagen gene promoter. Essentially, the levels of SIP1, collagen type 1 and 3, and α-SMA exhibit an inverse relationship with each other21. Additionally, a study by Kato et al. revealed that in hypertrophic scars, increased expression of miR-192 directly inhibits SIP1 protein in the TGF-β/Smad2-3 signaling pathway, leading to enhanced expression of collagen type 1 and 3, as well as α-SMA22.
In laboratory settings, elevating the levels of collagen peptides in skin fibroblast cells has been shown to stimulate the synthesis of elastin and suppress matrix metalloproteinase enzymes like MMP1 and MMP3. This effect is beneficial as it enhances the proliferation of fibroblast cells and increases the production of the extracellular matrix derived from these cells. 23. Moreover, the application of peptides derived from human COL1A2 in experimental conditions has demonstrated an augmentation in collagen levels, enhanced cell migration, and an increase in elastin content within skin fibroblast cells24.
The combination of PRP and HDFs expressing miR-192 was found to effectively alleviate symptoms of RA. This treatment resulted in a decrease in paw volume, arthritis score, and levels of RF and anti-CCP. Bouff et al. also25 observed similar results in their study, where the injection of autologous mouse skin fibroblasts led to increased production of anti-inflammatory cytokines. This resulted in a reduction in foot volume and arthritis score. The hypothesis proposed suggests that fibroblasts can effectively stimulate T helper 2 cell responses.
Furthermore, Ana Chee et al26 in their study demonstrated that human skin fibroblasts can suppress inflammation in an experimental model of intervertebral disc degeneration. This suppression is achieved by reducing the levels of cytokines and inflammatory chemokines such as CCL2 and IL-8. Additionally, fibroblasts prevent the recruitment of inflammatory cells, particularly neutrophils, to the site of injury. The increased expression of collagen type 1 and 2 by fibroblasts also contributes to the improvement and repair of intervertebral disc degeneration.
Emerging intra-articular therapies like PRP have been extensively researched for managing musculoskeletal injuries, showcasing positive outcomes in pain relief, functional improvement, and evidence of mitigating inflammatory changes while expediting the healing process. Moreover, no significant adverse effects associated with PRP treatment have been reported in numerous studies conducted thus far8. Aniss et al. 27 and Tong et al. 28 conducted studies demonstrating that a single intra-articular injection of autologous PRP administered during the second week after immunization can effectively suppress inflammation in an experimental model of rheumatoid arthritis. This suppression was observed through the reduction of inflammatory cytokines such as IL-6, IL-1β, and TNF-α. On the other hand, in the present study, combined treatment with PRP and HDFs expressing miR-192 improved RA-related parameters in ankle synovial tissue.
PRP is a composite of various growth factors that exhibit distinct effects on tissue regeneration. For instance, the growth factor EGF (epidermal growth factor) has been shown to enhance bone proliferation. Conversely, TGF (transforming growth factor) plays a significant role in stimulating the synthesis of proteoglycans in cartilage by inhibiting IL-1 (interleukin-1). Moreover, PDGF (platelet-derived growth factor) and IGF (insulin-like growth factor) are essential growth factors involved in the synthesis of proteoglycans and the proliferation of chondrocytes. These growth factors stimulate the production of extracellular matrix components, particularly proteoglycans, which are crucial for maintaining the structure and function of cartilage. Additionally, they facilitate the proliferation and survival of chondrocytes, thereby contributing to the processes of cartilage repair and regeneration3.
Aniss et al27 conducted a study where arthritic mice were treated with a combination of PRP and HA (hyaluronic acid) via intra-articular injection. This treatment led to a decrease in inflammatory cell infiltration, synovial hyperplasia, and cartilage degradation in the synovial tissue. In the study by Bouff et al.,25 rats with rheumatoid arthritis were systemically treated with mouse skin fibroblast cells like MSCs (mesenchymal stem cells). The histological score of stained ankles in these rats showed a reduction compared to the negative control group, although the reduction was not statistically significant. In the current study, the group treated with HDFs expressing miR-192 exhibited a decrease in the infiltration of inflammatory cells and cartilage destruction in the synovium. This can be attributed to the heightened expression of miR-192 and collagen in HDFs.
Ahmad et al29 conducted a study utilizing a combination therapy of PRP (platelet-rich plasma) and adipose-derived mesenchymal stem cells (AD-MSCs) in an animal model of osteoarthritis. Their findings demonstrated that when compared to the individual administration of PRP or AD-MSCs, the combined therapy led to a notable decrease in inflammatory cytokines such as IL-6 and TNF-α in the serum. Moreover, it elevated the levels of proteoglycans and collagen within the knee joint. This dual therapeutic strategy exhibits promise as a potential intervention for the management of cartilage-related disorders, fostering the processes of repair and regeneration.