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  • It is well known that

    2021-11-30

    It is well known that TNF-α plays a pivotal role in the pathogenesis of RA. TNF-α influences diverse pathologic processes including joint destruction as well as inflammatory responses [16]. While TNF-α significantly increases the levels of sFas and mFas expression from FLS, IL-1β and IL-17 have minimal effects on sFas induction. The expression of decoy receptor 3 (DCR3), which binds to FasL and protects against Fas-mediated apoptosis, was reported previously to be increased by TNF-α [10]. It is interesting that the authors of that study noted a similar mechanism of resistance against Fas signaling in which FasL might be blocked by binding to sFas. To examine apoptosis in FLS in our present study, flow cytometric analysis was performed (Fig. 1). Early events during apoptosis were detected by Annexin V staining. Annexin V binds preferentially to phosphatidylserine and other negatively-charged phospholipids, which are normally present in the inner leaflet of the plasma membrane and are exposed to the outer leaflet during early apoptosis [3], [31]. Thus, early apoptosis and late apoptosis/necrosis could be discriminated by Annexin V+, 7-AAD− and Annexin V+, 7-AAD+, respectively. Since most earlier studies used the TUNEL assay or lactate dehydrogenase (LDH) assay to detect apoptosis [11], [12], [18], some portions of early apoptotic many years might have been underestimated previously. This is a particularly important consideration because we here observed that the response to Fas triggering was more pronounced during early apoptosis than late apoptosis/necrosis in RA FLS (Fig. 1). There is insufficient evidence at this time to conclude that sFas is the principal factor for resistance to Fas-mediated apoptosis in vivo. A recent study investigating the role of membrane-bound FasL (mFasL) versus secreted FasL in apoptosis showed that only mFasL, but not the secreted form of FasL, triggered a Fas-dependent apoptotic pathway [20]. In addition, TNF-α could have direct effects on apoptosis and on cellular proliferation [32], and TNF-α also can affect cellular homeostasis via a number of pro-inflammatory responses, including cellular differentiation, adhesion and migration of inflammatory cells into the inflamed tissue [5], [19]. Indeed, cellular homeostasis is complex, and apoptosis can be influenced by various factors including interaction with neighboring cells expressing FasL on their cell surface [25]. Surely, it will be necessary in the future to address the potential effects of TNF-α on the apoptosis of cells other than FLS, including inflammatory cells.
    Conclusion In conclusion, we have here demonstrated that high levels of sFas and sFasL are present in the synovial fluid of RA patients. Furthermore, TNF-α, which was readily detected in the synovial cavity of RA, significantly induces sFas from FLS. Hence, sFas induction by TNF-α in vivo could account for the imbalance in apoptosis in FLS, resulting in the synovial hyperplasia of RA.
    Conflict of interest statement
    Acknowledgment This study was supported by a grant (2014–330) from the Asan Institute for Life Sciences, Seoul, Korea.
    Introduction Rheumatoid arthritis (RA) develops when the synovial lining of joints in the body are infiltrated by leukocytes, plasma cells, lymphocytes, endothelial cells, and activated macrophages that mediate induction of a chronic inflammatory state (Fig. 1) [1], [2]. Bone erosions often accompany the development of an inflammatory state in many rheumatic diseases and these destructive bone lesions develop when a break in cortical bone has occurred. Loss of adjacent trabecular and cortical bone structures proximal to a bone lesion generally occur due to osteoclastic bone resorption, a reduction in articular cartilage, and bone marrow edema [3], [4]. The latter can be detected with magnetic resonance imaging (MRI) [5], [6]. In RA, the size and number of erosions that are present in affected joints may be an indicator of the extent of damage that has occurred. Bone erosions represent the contribution of the bone marrow compartment to the destruction of bone and the promotion of cytokines involved in pro-inflammation [7], [8]. Osteoclasts are multinucleated myeloid lineage cells that are able to resorb bone, and these cells are essential for the remodeling and regeneration of bone. In degenerative diseases such as arthritis, osteoporosis, and cancer bone metastasis, the presence of an excessive number of osteoclasts has been found to contribute to bone destruction [9].