Search

Objectives Bone destruction is a remarkable feature of inflammatory arthritis. It remains unknown why arthritis associated with the systemic autoimmune/inflammatory condition systemic lupus erythematosus (SLE) does not result in erosion and destruction. We aimed to determine the role of autoantibody in the pathogenesis of non‐erosive arthritis in SLE. Methods We analysed medical record of SLE patients, investigated whether autoantibody induces arthritis lacking bone destruction in animal models and determined whether SLE autoantibody inhibits osteoclastogenesis induced by RANKL in vitro experiments. Results We found that arthritis lacking bone erosions is common in SLE patients and lupus‐prone mice. Intraarticular injection of lupus serum or IgG induces immune complex deposition and arthritis, but does not result in bone destruction. Deposition of IgG, monocytes/macrophages and TNF‐α is all required for the development of arthritis. Lupus serum or IgG inhibits RANKL‐induced differentiation of monocytes into osteoclast in a dose‐dependent manner. FcγR acts as co‐receptors for RANKL and is involved in osteoclastogenesis. Deficiency of FcγRII or FcγRIII does not affect osteoclastogenesis in the presence of SLE IgG. However, lupus IgG competes for FcγRI binding with RANKL, thereby reducing osteoclastogenesis. Conclusion Observations from this study demonstrate that IgG from SLE patients can induce arthritis and inhibits RANKL‐induced osteoclastogenesis through competitive occupation of FcγRI on monocytes/macrophages. This study improves the understanding of the pathophysiology of SLE‐associated arthritis and offers a protective mechanism (FcγRI inhibition) that may be targeted in other forms of autoimmune/inflammatory arthritis, such as RA, to prevent or limit bone erosion and inflammatory bone loss., In this study, we found that lupus IgG deposition in joints can induce synovial inflammation. Recruitment of lupus IgG to FcγRI may result in functional deficiency of FcγRI on the cellular membrane, which is required for RANKL‐induced osteoclastogenesis. Thus, joint deposited lupus IgG induces arthritis while inhibiting bone erosion.

A variety of biological functions of estrogens, including regulation of energy metabolism, are mediated by neurons expressing estrogen receptor-α (ERα) in the brain. However, complex intracellular processes in these ERα-expressing neurons are difficult to unravel, due to the lack of strategy to visualize ERα-expressing neurons, especially in unfixed brain tissues.Here we generated a novel ERα-ZsGreen reporter mouse line in which expression of a green fluorescent reporter protein, ZsGreen, is driven by a 241kb ERα gene promoter. We validated that ZsGreen is highly colocalized with endogenous ERα in the brain. Native ZsGreen signals were visualized in unfixed brain tissue, and were used to assist single cell collection and electrophysiological recordings. Finally, we demonstrated that this ERα-ZsGreen mouse allele can be used in combination with other genetic reporter alleles to allow experiments in highly selective neural populations.

Sexual dimorphism exists in energy balance, but the underlying mechanisms remain unclear. Here we show that the female mice have more pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus than males, and female POMC neurons display higher neural activities, compared to male counterparts. Strikingly, deletion of the transcription factor, TAp63, in POMC neurons confers “male-like” diet-induced obesity (DIO) in female mice associated with decreased POMC neural activities; but the same deletion does not affect male mice. Our results indicate that TAp63 in female POMC neurons contributes to the enhanced POMC neuron functions and resistance to obesity in females. Thus, TAp63 in POMC neurons is one key molecular driver for the sexual dimorphism in energy homeostasis., Sexual dimorphism exists in a number of physiological processes, including energy homeostasis. Here, the authors show that pro-opiomelanocortin neurons in female mice fire more rapidly than males, and that deletion of the transcription TAp63 leads to a reduced neuronal firing rate and a male-like susceptibility to diet-induced obesity.

Binge eating afflicts approximately 5% of US adults, though effective treatments are limited. Here, we showed that estrogen replacement substantially suppresses binge-like eating behavior in ovariectomized female mice. Estrogen-dependent inhibition of binge-like eating was blocked in female mice specifically lacking estrogen receptor-α (ERα) in serotonin (5-HT) neurons in the dorsal raphe nuclei (DRN). Administration of a recently developed glucagon-like peptide-1–estrogen (GLP-1–estrogen) conjugate designed to deliver estrogen to GLP1 receptor–enhanced regions effectively targeted bioactive estrogens to the DRN and substantially suppressed binge-like eating in ovariectomized female mice. Administration of GLP-1 alone reduced binge-like eating, but not to the same extent as the GLP-1–estrogen conjugate. Administration of ERα-selective agonist propylpyrazole triol (PPT) to murine DRN 5-HT neurons activated these neurons in an ERα-dependent manner. PPT also inhibited a small conductance Ca2+-activated K+ (SK) current; blockade of the SK current prevented PPT-induced activation of DRN 5-HT neurons. Furthermore, local inhibition of the SK current in the DRN markedly suppressed binge-like eating in female mice. Together, our data indicate that estrogens act upon ERα to inhibit the SK current in DRN 5-HT neurons, thereby activating these neurons to suppress binge-like eating behavior and suggest ERα and/or SK current in DRN 5-HT neurons as potential targets for anti-binge therapies.

Systemic lupus erythematosus (SLE) is a multiple organ autoimmune disorder, including the liver, but the possible reason in impairment in the liver is still unclear. Our present study assessed alterations of transcription factor Foxp3(+) regulatory T cells (Tregs) and several other immune molecules [programmed cell death 1 and its ligand (PD1 and PD-L1), and interleukin 10 (IL-10) and transform growth factor β (TGF-β)] in the liver and other major organs of lupus-prone BXSB mice by flow cytometry, real-time quantitative reverse transcription PCR, and enzyme-linked immunosorbent assay. Results showed that both frequency and number of Foxp3(+) Tregs were dramatically reduced in the thymus, spleen and kidney of the BXSB mice (P0.05), but those in the liver were kept in nearly normal range, when compared to negative control C57BL/6 mice. In comparison to control mice, the mRNA levels of Foxp3, PD1 and PD-L1 were significantly decreased in the kidneys of BXSB mice (P0.05), but there was no significant difference in the livers of the BXSB mice (P0.05). Protein levels of IL-10 and TGF-β in serum showed no significant difference between BXSB and C57BL/6 mice, but were significantly increased in the kidneys and livers of BXSB mice as compared with those in C57BL/6 mice (P0.05). These results suggest that reduced Foxp3(+) Tregs are involved in the pathogenesis of SLE in BXSB mice, and relatively higher number of these cells in the livers than in the other target organs could constitute a protective mechanism against hepatic lesions in lupus-prone mice, which may provide insights into development of new therapeutic approaches in SLE patients.

Background/Aims: Apolipoprotein A-IV (apoA-IV) in the brain potently suppresses food intake. However, the mechanisms underlying its anorexigenic effects remain to be identified. Methods: We first examined the effects of apoA-IV on cellular activities in hypothalamic neurons that co-express agouti-related peptide (AgRP) and neuropeptide Y (NPY) and in neurons that express pro-opiomelanocortin (POMC). We then compared anorexigenic effects of apoA-IV in wild-type mice and in mutant mice lacking melanocortin 4 receptors (MC4Rs; the receptors of AgRP and the POMC gene product). Finally, we examined expression of apoA-IV in mouse hypothalamus and quantified its protein levels at fed versus fasted states. Results: We demonstrate that apoA-IV inhibited the firing rate of AgRP/NPY neurons. The decreased firing was associated with hyperpolarized membrane potential and decreased miniature excitatory postsynaptic current. We further used c-fos immunoreactivity to show that intracerebroventricular (i.c.v.) injections of apoA-IV abolished the fasting-induced activation of AgRP/NPY neurons in mice. Further, we found that apoA-IV depolarized POMC neurons and increased their firing rate. In addition, genetic deletion of MC4Rs blocked anorexigenic effects of i.c.v. apoA-IV. Finally, we detected endogenous apoA-IV in multiple neural populations in the mouse hypothalamus, including AgRP/NPY neurons, and food deprivation suppressed hypothalamic apoA-IV protein levels. Conclusion: Our findings support a model where central apoA-IV inhibits AgRP/NPY neurons and activates POMC neurons to activate MC4Rs, which in turn suppresses food intake.

A novel non-synonymous (Gly307Ser) variant, rs763361, of the CD226 gene on chromosome 18q22 was recently shown to be associated with multiple autoimmune diseases. Taking into consideration that different autoimmune diseases may share some common pathogenic pathways, in this study we performed case-control studies to assess any genetic linkage with systemic lupus erythemtosus (SLE). An association between the Gly307Ser single nucleotide polymorphism (SNP) and susceptibility to SLE was identified. The TT genotype [odds ratio (OR) = 1.79, 95% confidence interval (CI) = 1.07-3.01, P = 0.025] and the T allele (OR = 1.34, 95% CI = 1.05-1.74, P = 0.018) of the rs763361 SNP were associated with the risk of SLE. This finding indicates that polymorphism of Gly307Ser (rs763361) in exon 7 of the CD226 gene may be associated with the development of SLE.

Recent case-control studies have identified some loci that are associated with rheumatoid arthritis (RA). Among these, a single nucleotide polymorphism (SNP), Gly307Ser (rs763361), in the CD226 gene was first discovered to confer the risk of RA in populations with European and Colombian ancestry. Because the effect of genetic factors varies in different races, the association between RA and CD226 is yet to be evaluated in other non-European populations. Here, we report the significant association between CD226 and RA in a Chinese population of 423 randomly enrolled individuals. The statistical results show that the rs763361 SNP in the CD226 gene is significantly associated with RA in the Chinese population group (P (obs) = 0.005, odds ratio = 1.52). After adjusting for sex and age using multivariate logistics regression analysis, the association is still positive (P (adj) = 0.029, odds ratio = 1.45). Meta-analysis confirms the association between rs763361 and RA (overall P < 0.001, overall odds ratio = 1.12). The test of odds ratio heterogeneity also suggests that the rs763361 SNP confers the same risk of RA in both the Chinese and the Colombian populations, and indicates that rs763361 may play a more important role in non-European populations compared with the European population (P = 0.031). These results demonstrate a genetic association between the CD226 gene and RA in a Chinese Han population with a potentially greater genetic effect than in the European population.

By means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, the association between vitamin D receptor (VDR) genotypes and bone mineral density (BMD) in the patients receiving long-term glucocorticoid therapy was studied. The clinical data and blood of 71 patients with rheumatosis who received long-term glucocorticoid therapy were collected. BMD was measured by dual-energy X-ray absorptimometry. VDR gene fragment (about 185 bp) was amplified by PCR from the extracted genomic DNA, then digested with restriction endonuclease Bsm I. The genotypes were evaluated based on the fragment length following endonuclease digestion and the association between genotypes and BMD or Z-score values was analyzed. Among the 71 cases, the detected genotypes were Bb and bb with the distribution frequency being 11.3% and 88.7% respectively. The distribution frequency of the alleles was in agreement with the Hardy-Weinberg equilibrium. There was no significant difference between the two genotypes in age, gender, body mass index (BMI), disease duration, disease types, time of glucocorticoid administration and cumulative dosage (P0.05). Osteoporosis rate of the patients with Bb or bb genotype was 37.5% and 33.3% respectively, with the difference being not significant (chi 2 = 0.05, P = 0.8). The BMD and Z-score values at lumbar spine and femur in two genotypes were not similar, but the difference had no significant (P0.05). The distribution frequency of bb type of VDR genotypes in Han populations of China was more prevalent, followed by Bb and bb types in turn. In the patients receiving long-term glucocorticoid therapy, there was no significant difference in BMD between Bb and bb genotypes. The data suggest that the VDR genotypes may not be means of identifying patients at greater risk of glucocorticoid-induced osteoporosis, which await to be further confirmed by a large sample size.