Abstract
Hyperplasia of synovial membrane in rheumatoid arthritis (RA) is a critical pathological foundation for inducing articular injury. The janus kinase and signal transducer and activator of transcription (Jak-STAT) pathway plays a critical role in synovial membrane proliferation induced by platelet-derived growth factor (PDGF). To explore the anti-cell proliferation mechanism of curcumol, a pure monomer extracted from Chinese medical plant zedoary rhizome, the changes of Jak2-STAT1/3 signal pathway-related molecules in synoviocytes were observed in vitro. In this study, the fibroblast-like synoviocytes (FLS) in patients with RA were collected and cultured. The following parameters were measured: cell proliferation (WST-1 assay), cell cycles (fluorescence-activated cell sorting, FACS), STAT1 and STAT3 activities (electrophoretic mobility shift assay, EMSA), and the protein expressions of phosphorylated Jak2, STAT1, and STAT3 (Western blot). It was shown that curcumol could inhibit the RA-FLS proliferation and DNA synthesis induced by PDGF-BB in a dose-dependent manner in vitro. The transcription factors activities of STAT1 and STAT3 were obviously elevated after PDGF-BB stimulation (P < 0.05). Super-shift experiments identified the STAT1 or STAT3 proteins in the complex. Furthermore, the different concentration curcumol could downregulate the DNA binding activities of STAT1 and STAT3 (P < 0.05) and inhibit the phosphorylation of Jak2 while it had no effect on the protein expressions of STAT1 and STAT3. Positive correlations were found between changes of cell proliferation and DNA-binding activities of STAT1 and STAT3, respectively (P < 0.01). In conclusion, curcumol might suppress the FLS proliferation and DNA synthesis induced by PDGF-BB through attenuating Jak2 phosphorylation, downregulating STAT1 and STAT3 DNA-binding activities, which could provide theoretical foundation for clinical treatment of RA.
Highlights
Rheumatoid arthritis (RA) is a chronic destructive disease of the joints that is characterized by chronic proliferative synovitis, infiltration of inflammatory cells into the synovial tissue of joints, and cartilage destruction
Compared to the platelet-derived growth factor (PDGF)-BB group, cell proliferation and DNA synthesis of Fibroblast-like synoviocytes (FLS) changed very significantly in the groups treated with curcumol (P < 0.01)
As a potent strategy to protect against carcinogenesis, phytochemicals in Chinese medicine herbs have been applied to protect against carcinogenesis through acting on diverse cellular events including regulation of apoptosis [21]
Summary
Rheumatoid arthritis (RA) is a chronic destructive disease of the joints that is characterized by chronic proliferative synovitis, infiltration of inflammatory cells into the synovial tissue of joints, and cartilage destruction. Fibroblast-like synoviocytes (FLS) and inflammatory cells, such as macrophages and T cells, produce proinflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor-α, which play key roles in the pathogenesis of RA [1]. RA synovial tissues or cells are not truly malignant, but they have many features of transformation, denoted as “partial transformation”. These features include anchorage-independent growth, loss of contact inhibition, oncogene activation, monoclonal or oligoclonal expansion, detectable telomerase activity, and somatic gene mutations [2, 3]. Therapies used in the treatment of tumors may be effective in the treatment of RA. Clinical experience shows that RA treatment may be more effective than simple
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