| Part ⅠFibroblast-like synoviocytes from rheumatoid arthritisRheumatoid arthritis (RA) remains an unsolved medical problem despite multiple therapeutic advances. The pathogenesis of RA is complex, and many cell types, including T cells, B cells, and macrophages are included. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role in the pathogenesis of RA by producing inflammatory cytokines and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that invades into the extracellular matrix and further exacerbates joint injury. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies.Part ⅡFurin-embryogenesis and diseasesAlthough furin catalyses a simple biochemical reaction, which is the proteolytic maturation of proprotein substrates in the secretory pathway, the simplicity of this reaction belies furin’s broad and important roles in homeostasis, as well as in diseases ranging from Alzheimer’s disease and cancer to anthrax and Ebola fever. This review summarizes various features of furin, including its structural and enzymatic properties, intracellular localization, trafficking, substrates, and roles in embrogenesis and diseases.Part ⅢInhibition of furin results in increased growth and invasiveness of synoviocytes from patients with rheumatoid arthritisRheumatoid arthritis (RA) is characterized by chronic inflammation in synovium and destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining play a key role by local production of cytokines, mediators of inflammation, and proteolytic enzymes that degrade the extracellular matrix and cartilage. FLS derived from RA synovium acquire phenotypic characteristics commonly observed in transformed cells, like anchorage-independent growth, increased proliferation and invasiveness, and insensitivity to apoptosis. Furin is a ubiquitous proprotein convertase that is capable of cleaving precursors of a wide variety of proteins, including growth factors and their receptors and proteinases. In RA patients, furin is reported to be highly expressed in the synovial pannus compared with healthy persons. The mechanisms and functions of furin overexpression in RA synoviocytes are poorly understood. In this study, RNA interference was used to knock down furin expression and to assess the resultant effects on FLS biological behaviors. The results showed that the inhibition of furin enhanced FLS proliferation, invasion, and migration in vitro. Cell cycle was accelerated and cell death was affected by furin knockdown. Also, the inhibition of furin increased interleukin-1β and tumor necrosis factor-a secretion in FLS. This study highlights a pivotal role for furin in the biological behaviors of rheumatoid FLS, especially the invasive ability and cytokine production. And furin is identified as a potential target to inhibit the invasive phenotype of FLS in RA.Part ⅣInhibition of PCSK6 results in decreased growth and invasiveness of synoviocytes from patients with rheumatoid arthritisPCSK6 is a proteinase implicated in the proteolytic activity of various precursor proteins and involved in the regulation of protein maturation. Cultured RA synovial fibroblasts FLS were transfected with PCSK6 small interfering RNA to study changes in the proliferation, invasion, migration capacity, secretion of inflammatory cytokines of the RASF. Results showed that knockdown of PCSK6 by RNA interference significantly decreased proliferation, invasion, and migration of RASF. These changes in RASF appeared to be related to reduced tumor necrosis factor-α secretion. In conclusion, inhibition of PCSK6 may play a protective role in the development of RA. |
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