Feng-Lai Yuan

Targeting interleukin-21 in rheumatoid arthritis

Interleukin-21 (IL-21) is a new member of the type I cytokine superfamily, which binds to a composite receptor that consists of a private receptor (IL-21R) and the common cytokine receptor γ chain. Recently, increasing evidence has shown that IL-21 contributes to the pathogenesis of chronic inflammatory and autoimmune diseases because of its pro-inflammatory and immune-mediated properties. IL-21 induced T-cell activation and pro-inflammatory cytokine secretion in rheumatoid arthritis (RA). IL-21R RNA transcripts were found in synovial tissue samples of patients with RA. In addition, blockade of the IL-21/IL-21R pathway ameliorated disease in animal models of RA and significantly inhibited inflammatory cytokine production in vitro. Moreover, IL-21R deficiency in the K/BxN mouse model of inflammatory arthritis was sufficient to block arthritis initiation completely. All theses findings suggest that IL-21 has important biological effects in autoimmunity that might be a promising therapeutic target for RA. In this review, we discuss the biological features of IL-21 and summarize recent advances in the role of IL-21 in the pathogenesis and treatment of RA.

Blockade of acid-sensing ion channels protects articular chondrocytes from acid-induced apoptotic injury

ObjectiveAcid-sensing ion channels (ASICs) are members of the degenerin/epithelial sodium channel (DEG/ENaC) protein superfamily and play a critical role in acid-induced cell injury. In this study, we examined whether drugs such as amiloride that block ASICs could attenuate acid-induced apoptotic injury to articular chondrocytes.MethodsArticular chondrocytes were isolated from Sprague–Dawley rats, and their phenotype was determined by toluidine blue and immunocytochemical staining. Articular chondrocyte viability assay was performed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). Apoptosis of chondrocytes was observed by the terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling method as well as propidium iodide labeling methods. Intracellular calcium ([Ca2+]i) was analyzed by a Ca2+-imaging method. In addition, the expression levels of calpain and calcineurin in articular chondrocytes were examined by real-time PCR and immunocytochemical staining. The activity of caspase-3 was evaluated by spectrophotometric assays.ResultsPositive staining for glycosaminoglycan and collagen II was seen in articular chondrocytes. Blocking acid-sensing ion channels significantly decreased the cell death percentage and increased cell viability following acid exposure. After pretreated with amiloride, acid-induced [Ca2+]i rises were reduced. Amiloride also inhibited calpain and calcineurin expression levels in acid-induced chondrocytes, and inhibited caspase-3 activity.ConclusionThe data presented in this study provided some experimental evidence that blocking ASICs could protect acid-induced apoptotic injury to chondrocytes.

Acid-sensing ion channel 1a is involved in acid-induced osteoclastogenesis by regulating activation of the transcription factor NFATc1

It has been known that osteoclastogenesis is induced by extracellular acidosis‐evoked the rise of intracellular calcium ([Ca2+]i), which regulate activation of the transcription factor nuclear factor of activated T cells c1 (NFATc1). However, the acid‐sensing ion channels (ASICs) involved remain largely unknown. Here, we show that ASIC1a, ASIC1b, ASIC2a, and ASIC3 are expressed in rat osteoclasts, and only ASIC1a is highly upregulated in response to acidosis. Both the ASIC1a‐specific blocker PcTX1 and specific siRNA significantly reduce this increase in acid‐induced [Ca2+]i and acid‐induced nuclear translocation of NFATc1, and inhibit acid‐induced osteoclast differentiation and bone resorption. These findings show that ASIC1a‐mediated calcium entry plays a critical role in osteoclastogenesis by regulating activation of the NFATc1.

IL-33: a promising therapeutic target for rheumatoid arthritis?

Cytokine-mediated immunity plays a crucial role in the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA). Recently, the IL-1-family-related cytokine, IL-33, was detected at high levels in experimental inflammatory arthritis and in the early phase of human RA, and was reported to exert profound pro-inflammatory effects in several experimental autoimmune models. Moreover, administration of IL-33 leads to the development of severe inflammatory arthritis, suggesting that IL-33 may be therapeutically relevant in RA, and the targeting of IL-33 or the IL-33 receptor has been proposed as a potential therapeutic approach for autoimmune diseases such as RA. In this article, we discuss the biological features of IL-33 and summarize recent advances in our understanding of the role of IL-33 in the pathogenesis and treatment of RA. It is hoped that this information may aid the development of novel therapeutic strategies for RA.

Leonurine hydrochloride inhibits osteoclastogenesis and prevents osteoporosis associated with estrogen deficiency by inhibiting the NF-κB and PI3K/Akt signaling pathways

Osteoclasts, the primary bone resorbing cells, are responsible for destructive bone diseases such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis. Many plant-derived traditional medicines that might suppress the formation and/or function of osteoclasts are promising treatments for osteoclast-related diseases. In this study, we investigated the effects of leonurine hydrochloride (LH) on receptor activator NF-κB ligand (RANKL)-induced osteoclastogenesis and ovariectomy-induced bone loss. LH is a synthetic chemical compound based on the structure of leonurine, which is found in motherwort and has been reported to exhibit phytoestrogenic activity. In RAW 264.7 cells and mouse bone marrow monocytes (BMMs), LH suppressed RANKL-induced osteoclastogenesis and actin ring formation in a dose-dependent manner. LH targeted RANKL-induced osteoclastogenesis and bone resorption at an early stage. Molecular analysis demonstrated that LH attenuated RANKL-induced NF-κB signaling by inhibiting the phosphorylation and degradation of IκBα and NF-κB p65 nuclear translocation. LH inhibited the RANK-TRAF6 association triggered by RANKL binding and the phosphatidylinositol 3-kinase (PI3K)/Akt axis, without significantly affecting the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and AP-1 signaling pathways. LH attenuated the RANKL-stimulated expression of osteoclast-related genes including NFATc1, tartrate resistant acid phosphatase (TRAP), cathepsin K, and osteoclast-associated receptor (OSCAR). Consistent with the in vitro results, LH administration attenuated osteoclast activity, thus preventing bone loss caused by estrogen deficiency in mice. In this study, LH suppressed RANKL-induced osteoclastogenesis via RANK-TRAF6, NF-κB, and PI3K/Akt signaling. These data provide the first evidence that LH might be a promising therapeutic compound to treat osteoclast-related diseases, such as osteoporosis.

Type 17 T-helper cells might be a promising therapeutic target for osteoporosis

Osteoporosis, a disease characterized by low bone mass and deterioration of bone tissue, is a pressing public health problem. Recent studies have suggested a possible role of T-helper (Th) cells in the pathogenesis of bone loss which occurs in systemic inflammatory diseases. However, there are contradictions in the published literature regarding the functional role of Th1/Th2 cells in the regulation of the differentiation of osteoclasts. These paradoxes have now been clarified by the recent discovery of Th17 cells, a novel subset of Th cells that selectively secrete several proinflammatory cytokines, mainly IL-17. It has been confirmed that Th17 cells have stimulatory effects on osteoclastogenesis and accelerate bone loss in animal models with inflammatory disorders. Targeting Th17 cells or IL-17 may inhibit the bone resorption with RA. Thus, we are led to suppose that Th17 cells might be promising therapeutic targets in osteoporosis.

Effects of leonurine hydrochloride on medically induced incomplete abortion in early pregnancy rats.

OBJECTIVES To determine the effect of leonurine hydrochloride (LH) on abnormal bleeding induced by medical abortion. STUDY DESIGN Rats had incomplete abortions induced in early pregnancy using mifepristone in combination with misoprostol. After abortion, rats were treated with LH for 7 days, and the duration and volume of uterine bleeding were observed. Approximately 30min after the last treatment, the animals were killed and the uterine shape was observed. The sinistro-uteri were suspended in organ baths to record the contraction curves, including the frequency and tension for 10min; the dextro-uteri were fixed with formaldehyde for pathologic evaluation. In addition, blood samples were collected from the femoral artery for the measurement of estradiol (E₂) and progesterone (P) levels by radioimmunoassay. RESULTS In in vivo experiments, compared with the model group, LH treatment markedly reduced the volume of bleeding and intrauterine residual, and significantly shortened the duration of bleeding. From the contraction curve, LH notably reinforced the frequency and tension of uterine contractions. LH remarkably elevated the serum estradiol level in rats, but had no obvious effect on progesterone level. CONCLUSIONS LH has an inhibitory effect on bleeding caused by incomplete abortion; the mechanism may be related to up-regulation of the E₂ level, leading to an increase in uterine contractions and evacuation of intrauterine residuum.

Induction of autophagy by salidroside through the AMPK-mTOR pathway protects vascular endothelial cells from oxidative stress-induced apoptosis

Vascular endothelial cells are highly sensitive to oxidative stress, and this is one of the mechanisms by which widespread endothelial dysfunction is induced in most cardiovascular diseases and disorders. However, how these cells can survive in oxidative stress environments remains unclear. Salidroside, a traditional Chinese medicine, has been shown to confer vascular protective effects. We aimed to understand the role of autophagy and its regulatory mechanisms by treating human umbilical vein endothelial cells (HUVECs) with salidroside under oxidative stress. HUVECs were treated with salidroside and exposed to hydrogen peroxide (H2O2). The results indicated that salidroside exerted cytoprotective effects in an H2O2-induced HUVEC injury model and suppressed H2O2-induced apoptosis of HUVECs. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, increased oxidative stress-induced HUVEC apoptosis, while the autophagy activator rapamycin induced anti-apoptosis effects in HUVECs. Salidroside increased autophagy and decreased apoptosis of HUVECs in a dose-dependent manner under oxidative stress. Moreover, 3-MA attenuated salidroside-induced HUVEC autophagy and promoted apoptosis, whereas rapamycin had no additional effects compared with salidroside alone. Salidroside upregulated AMPK phosphorylation but downregulated mTOR phosphorylation under oxidative stress; however, administration of compound C, an AMPK inhibitor, abrogated AMPK phosphorylation and increased mTOR phosphorylation and apoptosis compared with salidroside alone. These results suggest that autophagy is a protective mechanism in HUVECs under oxidative stress and that salidroside might promote autophagy through activation of the AMPK pathway and downregulation of mTOR pathway.

Inhibition of acid-sensing ion channel 1a in hepatic stellate cells attenuates PDGF-induced activation of HSCs through MAPK pathway

Acid-sensing ion channels (ASICs), a group of Na+-selective and Ca2+-permeant ligand-gated cation channels, can be transiently activated by extracellular acid. Among seven subunits of ASICs, acid-sensing ion channel 1a (ASIC1a), which is responsible for Ca2+ transportation, is elevated in response to inflammation, tumor, and ischemic injury in central nervous system and non-neuronal tissues. In this study, we demonstrated for the first time the presence of ASIC1a in rat liver and hepatic stellate cells (HSCs). Furthermore, the expression of ASIC1a was increased in primary HSCs and liver tissues of CCl4-treated rats, suggesting that ASIC1a may play certain role in liver fibrosis. Interestingly, we identified that the level of ASIC1a was significantly elevated in response to platelet-derived growth factor (PDGF) induction in a time- and dose-dependent manner. It was also established that Ca2+-transporting ASIC1a was involved in acid-induced injury of different cell types. Moreover, inhibition or silencing of ASIC1a was able to inhibit PDGF-induced pro-fibrogenic effects of activated rat HSCs, including cell activation, de novo synthesis of extracellular matrix components through mitogen-activated protein kinase signaling pathway. Collectively, our studies identified that ASIC1a was expressed in rat liver and HSCs and provided a strong evidence for the involvement of the ASIC1a in the progression of hepatic fibrosis.

Epidermal growth factor receptor (EGFR) as a therapeutic target in rheumatoid arthritis.

The epidermal growth factor receptor (EGFR) has an important role in the hyperplastic growth of tumor. Similar to tumor growth, rheumatoid arthritis (RA) synovium is hyperplastic, invasive, and expresses EGFR and its ligands. Activation of EGFR signaling is responsible for synovial fibroblast proliferation in RA. Furthermore, in addition to its role in proliferation, EGFR and its ligands can induce cytokine production of synovial fibroblasts during the pathogenesis of RA. Agents that target EGFR have yielded promising results in animal experiments involving RA, pharmacologic modulations targeting EGFR, or its ligands may give rise to new therapeutic approaches for RA. In this review article, we will discuss the biological features of EGFR and summarize recent advances regarding the role of EGFR in the pathogenesis and treatment of RA.