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.

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.

The role of interleukin-17 in mediating joint destruction in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, persistent inflammatory joint disease with systemic involvement that affects about 1% of the world's population, that ultimately leads to the progressive destruction of joint. Effective medical treatment for joint destruction in RA is lacking because the knowledge about molecular mechanisms leading to joint destruction are incompletely understood. It has been confirmed that cytokine-mediated immunity plays a crucial role in the pathogenesis of various autoimmune diseases including RA. Recently, IL-17 was identified, which production by Th17 cells. IL-17 has proinflammatory properties and may promote bone and joint damage through induction of matrix metalloproteinases and osteoclasts. In mice, intra-articular injection of IL-17 into the knee joint results in joint inflammation and damage. In addition, it has been shown that blocking IL-17/IL-17R signaling is effective in the control of rheumatoid arthritis symptoms and in the prevention of joint destruction. In this article, we will briefly discuss the biological features of IL-17/IL-17R and summarize recent advances on the role of IL-17/IL-17R in the pathogenesis and treatment of joint destruction in RA.

Regulatory T cells as a potent target for controlling bone loss.

Metabolic bone diseases, such as rheumatoid arthritis (RA) and osteoporosis, affect hundreds and millions of people worldwide leading causes of long-term pain and disability. Effective clinical treatment for bone destruction in bone diseases is lacking because the knowledge about molecular mechanisms leading to bone destruction are incompletely understood. Recently, it has been confirmed that regulatory T cells (Tregs) play a crucial role in suppressing the immune response in the pathogenesis of various autoimmune diseases. In vitro, Tregs directly inhibit osteoclasts and differentiation and function. In mice, the injection of Tregs into the TNF transgenic results in enhanced systemic bone density. In addition, it has been shown that increase of Tregs numbers by overexpressing the FoxP3 is effective in the prevention of local and systemic bone destruction. In vivo treatment with anti-CD28 superagonist antibody leading to a stronger increase in Tregs numbers protect against TNF-a-induced bone loss in TNF-transgenic mice. In agreement, Tregs can control ovariectomy-induced bone loss in FoxP3-transgenic mice. In this paper, we will briefly discuss the biological features of Tregs and summarize recent advances on the role of Tregs in the pathogenesis and treatment of bone loss in metabolic bone diseases.

Acid-sensing ion channel 1a mediates acid-induced increases in intracellular calcium in rat articular chondrocytes.

Acid-sensing ion channels (ASICs) are cationic channels that are activated by extracellular acidification and implicated in pain perception, ischemic stroke, mechanosensation, learning, and memory. It has been shown that ASIC1a is an extracellular pH sensor in the central and peripheral nervous systems, but its physiological and pathological roles in non-neural cells are poorly understood. We demonstrated a novel physiological function of ASIC1a in rat articular chondrocytes. The expression of ASIC1a mRNA and protein in rat articular chondrocytes was evaluated by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. The distribution of ASIC1a protein located in articular chondrocytes was determined by using immunofluorescence cell staining. The possible molecular mechanisms of articular chondrocytes pH sensing, as assessed by recording intracellular calcium ([Ca(2+)]i) in chondrocytes, were analyzed by using the laser scanning confocal microscopy technique. The cell injury following acid exposure was analyzed with lactate dehydrogenase release assay and electron microscopy. mRNA and protein expression showed that ASIC1a was expressed abundantly in these cells. In cultured chondrocytes, extracellular pH 6.0 increased intracellular calcium in the presence of extracellular Ca(2+). The ASIC1a-specific blocker PcTX venom significantly reduced this increase in [Ca(2+)]i, and inhibited acid-induced articular chondrocyte injury. However, the increase in [Ca(2+)]i and articular chondrocyte injury were not observed in the absence of extracellular Ca(2+). These findings show that increased [Ca(2+)]i, mediated via ASIC1a, might contribute to acidosis-induced articular chondrocyte injury.

Inhibition of acid-sensing ion channels in articular chondrocytes by amiloride attenuates articular cartilage destruction in rats with adjuvant arthritis.

OBJECTIVE: The aim of this study was to examine whether drugs such as amiloride that block acid sensing ion channels (ASICs) could attenuate articular cartilage destruction in adjuvant-induced arthritis (AA). METHODS: Articular chondrocytes were isolated from the normal rats, and intracellular calcium ([Ca(2+)]i) was analyzed with laser scanning confocal microscopy. The cell injury was analyzed with lactate dehydrogenase release assay and electron microscopy. Amiloride or phosphate buffered saline was administered daily to AA rats for 1 week from the time of arthritis onset. Morphology of the articular cartilage was examined by hematoxylin and eosin staining, and Mankin score was calculated. The expression level of type II collagen (COII) and aggrecan mRNA and proteins in the articular cartilage was evaluated by real-time PCR and Western blotting, respectively. RESULTS: The rapid decrease in extracellular pH (6.0) induced a conspicuous increase in [Ca(2+)]i in the articular chondrocytes. Amiloride reduced this increase in [Ca(2+)]i, and inhibited acid-induced articular chondrocyte injury. Amiloride significantly decreased Mankin scores in the articular cartilage in AA rats. COII and aggrecan mRNA and protein expression in the articular cartilage was significantly increased by amiloride. CONCLUSION: These findings represent some experimental evidence of a potential role for ASICs in the pathogenesis of articular cartilage destruction in rheumatoid arthritis.

The vacuolar ATPase in bone cells: a potential therapeutic target in osteoporosis.

The vacuolar ATPase (V-ATPase) is a multisubunit enzyme that couples ATP hydrolysis to proton pumping across membranes. Recently, there is increasing evidence that V-ATPase may contribute to the pathogenesis of bone resorption disorders due to it is predominantly expressed in osteoclasts also function in bone resorption making it a good candidate in a therapeutic target for osteoporosis. Osteoclasts are capable of generating an acidic microenvironment necessary for bone resorption by utilizing V-ATPases to pump protons into the resorption lacuna. In addition, it has been shown that therapeutic interventions have been proposed that specifically target inhibition of the osteoclast proton pump. Modulation of osteoclastic V-ATPase activity has been considered to be a suitable therapy for the treatment of osteoporosis. All theses findings suggest that V-ATPase have important biological effects in bone resorption that might be a promising therapeutic target for osteoporosis. In this review, we will briefly discuss the biological features of osteoporosis and summarize recent advances on the role of V-ATPase in the pathogenesis and treatment of osteoporosis.

[Changes of leptin resistance, blood lipids and inflammatory response before and after the exercise therapy in children with obesity].

OBJECTIVE: Some research has shown that C-reactive protein (CRP), leptin, soluble leptin receptor (sLR) and blood lipids are involved in the development of obesity. This study aimed to investigate the changes of leptin resistance, blood lipids and inflammatory response before and after the exercise therapy in children with obesity. METHODS: Fifty-one obese children at ages of 12 years received an exercise therapy for 2 months. The levels of serum leptin, sLR, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP) were measured before and after the exercise therapy. Forty normal children served as the control group. RESULTS: Compared with the control group, serum levels of leptin, TG, TC, LDL-C and hs-CRP and the body mass index (BMI) in the obese group increased (p<0.01), while the serum level of sLR decreased significantly (p<0.05). The levels of hs-CRP, leptin, TC, TG, LDL-C and BMI in the obese group were significantly reduced after the exercise therapy (p<0.05). In the obese group, the serum leptin level was positively correlated with the levels of blood lipids and hs-CRP (p<0.05); serum levels of leptin and hs-CRP were negatively correlated with the sLR level (p<0.05); the hs-CRP level was positively correlated with the levels of blood lipids (p<0.01). CONCLUSIONS: Leptin resistance and the changes of blood lipids and inflammatory response are found in children with obesity. Exercise therapy can partially improve these changes.

Association of interleukin-18 and asthma.

Cytokine-mediated immunity plays a dominant role in the pathogenesis of various immune diseases, including asthma. The recent identification of the family interleukin (IL)-1-related cytokine IL-18 now contributes to our understanding of the fine-tuning of cellular immunity. IL-18 can act as a cofactor for Th2 cell development and IgE production and also plays an important role in the differentiation of Th1 cells. Recent work identified an IL-18 association with the pathogenesis of asthma, wherein increased IL-18 expression was found in the serum of patients. Furthermore, IL-18 polymorphisms with susceptibility to asthma were reported, suggesting that IL-18 may be therapeutically relevant to asthma. In this review, we discuss the role of IL-18 in the pathogenesis of asthma and its therapeutic potential based on current research.

Effect of leonurine hydrochloride on endothelin and the endothelin receptor-mediated signal pathway in medically-induced incomplete abortion in rats.

OBJECTIVE: Endothelin (ET) is involved in uterine contractions. Our previous study showed that leonurine hydrochloride (LH) inhibits abnormal bleeding caused by incomplete abortion through an increase in uterine contractions in rats. The present study was conducted to show that LH treatment regulates the ET-mediated signal pathway in abortion in rats. STUDY DESIGN: Early pregnancies in rats had incomplete abortions induced using mifepristone in combination with misoprostol. After the abortions, the rats were treated with LH orally for 7 days and surgery was performed. The sinistro-uterus was dissected for measurement of ET and nitric oxide (NO); the dextro-uterus was stored at -80°C for ET receptor (ETA and ETB) analysis. Myometrial cells from the dextro-uterus were cultured for measurement of phospholipase C (PLC) activity, intra-cellular Ca(2+) concentration ([Ca(2+)]i), and protein kinase C (PKC) activity. RESULTS: In in vivo experiments, LH treatment elevated the ET level and ET/NO ratio in rats with induced abortions and up-regulated ETA mRNA expression (P<0.01 vs. the model group), but there was no change in ETB mRNA. LH significantly increased the [Ca(2+)]i, PLC activity, and relative production of PKC protein in myometrial cells. CONCLUSION: LH increased uterine contractions in rats with incomplete abortions by modulating the ET receptor-mediated signal pathway.

T cell immunoglobulin-3 as a new therapeutic target for rheumatoid arthritis.

T cell immunoglobulin-3 (Tim-3) is a surface molecule expressed on various cell types of the immune system which plays a central role in immune regulation. Recently, identification of galectin-9 (Gal-9) as a ligand for Tim-3 has established the Tim-3-Gal-9 pathway as an important regulator of Th1 immunity and induction of tolerance. The interaction of Tim-3 with Gal-9 induces cell death; the in vivo blockade of this interaction results in exacerbated autoimmunity and abrogation of tolerance in experimental models, thus establishing Tim-3 as a negative regulatory molecule. A number of previous studies have demonstrated that Tim-3 influences chronic autoimmune diseases, such as multiple sclerosis and systemic lupus erythematosus. In addition, an association between Tim-3 polymorphisms and susceptibility to several autoimmune diseases has been identified in various autoimmune diseases, including rheumatoid arthritis (RA). Recent work has focused on the role of Tim-3 in RA, and the results indicate that Tim-3 may represent a novel target for the treatment of RA. In this article we will discuss the Tim-3 pathway and the therapeutic potential of modulating the Tim-3 pathway in RA.

The TNF-alpha-238 polymorphism and cancer risk: a meta-analysis.

BACKGROUND AND OBJECTIVES: Tumor necrosis factor-α (TNF-α) plays a very important role in the development and progress of cancer. Some TNF-α polymorphisms have been confirmed to increase cancer risks; however, the association between TNF-α-238 polymorphism and cancers remains controversial and ambiguous. The aim of this study is to explore a more precise estimation of its relationship with cancer using meta-analysis. METHODS: Electronic searches of several databases were conducted for all publications on the association between this variant and cancer through March 2011. Odds ratios (OR) with 95% confidence intervals (95% CI) were used to access the strength of this association in the random-effect model. RESULTS: Thirty four studies with 34,679 cancer patients and 41,186 healthy controls were included. This meta-analysis showed no significant association between TNF-α-238 polymorphism and cancers (AA+GA vs GG: OR = 1.09, 95%CI = 0.88-1.34). In Caucasian and Asian subgroups, OR values (95% CI) were 1.14 (0.91-1.43) and 0.97 (0.58-1.61), respectively. In the subgroups of cancer type, no significant association was detected. The sensitivity analysis further strengthened the validity of these negative associations. No publication bias was observed in this study. CONCLUSIONS: No significant association was found between the TNF-α-238 polymorphism and the risk for cancer.

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.

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.

Protective effects of Atractylodes macrocephala polysaccharide on liver ischemia-reperfusion injury and its possible mechanism in rats.

Atractylodes macrocephala polysaccharide (AMP), a traditional Chinese medicine, is thought to have protective effects against liver injury. Therefore, this study was designed to explore the effects of AMP on hepatic ischemia-reperfusion injury (IRI) and elucidate the possible mechanisms. Ninety-six Sprague-Dawley rats were randomly divided into four groups with 24 rats per group: a normal control group, an IRI group, an AMP-treated group (0.4 g/kg/d) and a bifendate-treated group (100 mg/kg). Rats were treated with AMP or bifendate once daily for seven days by gastric gavage. The normal control group and the IRI model group received an equivalent volume of physiological saline. At 1, 6 and 24 h after surgery, the rats were killed and liver tissue samples were obtained to determine interleukin-1 (IL-1) expression by Western blotting and nuclear factor-κB (NF-κB) expression by immunohistochemistry. Liver morphology was assessed by microscopy and transmission electron microscopy. Blood samples were obtained to measure liver function (alanine aminotransferase, aspartate aminotransferase, total bilirubin and direct bilirubin). AMP significantly reduced the elevated expression of markers of liver dysfunction and the hepatic morphologic changes induced by hepatic IRI in rats. AMP also markedly inhibited IRI-induced lipid peroxidation and altered the activities of the antioxidant enzyme superoxide dismutase and malondialdehyde levels. Moreover, pretreatment with AMP suppressed the expression of interleukin-1ß and NF-kB in IRI-treated rats. These results suggest that AMP exerts protective and therapeutic effects against hepatic IRI in rats, which might be associated with its antioxidant properties and inhibition of NF-κB activation. More studies are needed to better understand the mechanisms underlying the protective effects of AMP on hepatic IRI.

Association of NOD1 (CARD4) insertion/deletion polymorphism with susceptibility to IBD: a meta-analysis.

AIM: To find evidences about whether NOD1/CARD4 insertion/deletion polymorphism is associated with inflammatory bowel disease by meta-analysis. METHODS: We surveyed the studies on the association of NOD1/CARD4 insertion/deletion polymorphism with inflammatory bowel disease in PubMed. Meta-analysis was performed for genotypes GG/T vs T/T, GG/GG vs T/T, GG/T + GG/GG vs T/T, GG/GG vs T/T + GG/T, and GG allele vs T allele in a fixed/random effect model. RESULTS: We identified 8 studies (6439 cases and 4798 controls) in Caucasian populations using PubMed search. We found no association between NOD1/CARD4 insertion/deletion polymorphism and inflammatory bowel disease, Crohn's disease, and ulcerative colitis. Stratification of cases by age showed that NOD1/CARD4 insertion/deletion polymorphism was associated with inflammatory bowel disease in younger age group at onset (< 40 years) (GG vs T: OR = 0.68, 95% CI: 0.50-0.93, P = 0.02; GG/T + GG/GG vs T/T: OR = 0.71, 95% CI: 0.59-0.85, P = 0.0003). CONCLUSION: This meta-analysis demonstrates an association between NOD1/CARD4 insertion/deletion polymorphism and inflammatory bowel disease in the younger age group at onset (< 40 years) in Caucasian populations.