Inhibition of inflammation but not ankylosis by glucocorticoids in mice: further evidence for the entheseal stress hypothesis

Introduction

Studies in the spontaneous ankylosis model in aging male DBA/1 mice and in patients with ankylosing spondylitis provide evidence that inflammation and new tissue formation leading to joint or spine ankylosis are likely linked but largely uncoupled processes. We previously proposed the ''entheseal stress'' hypothesis that defines microdamage or cell stress in the enthesis as a trigger for these disease processes. Here, we further investigated the relationship between inflammation and ankylosis by focusing on the early phase of the spontaneous arthritis model.

Methods

Aging male DBA/1 mice from different litters were caged together at the age of ten weeks and studied for signs of arthritis. A group of DBA/1 mice were treated daily with dexamethasone (0.5 μg/g body weight). Severity of disease was assessed by histomorphology and by positron emission tomography (PET) using 2-[¹⁸F]fluoro-2-deoxy-D-glucose (¹⁸F-FDG) as a tracer. Bone loss in dexamethasone-treated or control mice was determined by in vivo dual-energy X-ray absorptiometry. Chemokine gene expression was studied ex vivo in dissected paws and in vitro in mesenchymal cells (periosteal and bone marrow stromal cells) by quantitative real-time PCR in the presence or absence of bone morphogenetic protein 2 (BMP2) and dexamethasone.

Results

Dexamethasone treatment did not affect incidence or severity of ankylosis, but led to an expected reduction in inflammation in the paws at week 15 as measured by PET tracer uptake. Treatment with dexamethasone negatively affected bone mineral density. Chemokines attracting neutrophils and lymphocytes were expressed in affected paws. In vitro, BMP2 stimulation upregulated chemokines in different mesenchymal joint-associated cell types, an effect that was inhibited by dexamethasone.

Conclusions

BMP signaling may be a trigger for both inflammation and ankylosis in the spontaneous model of ankylosing enthesitis. The lack of inhibition by glucocorticoids on new bone formation while causing systemic bone loss highlights the paradoxical simultaneous loss and gain of bone in patients with ankylosing spondylitis.     

Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors

Introduction

Ankylosing spondylitis (AS) is unique in its pathology where inflammation commences at the entheses before progressing to an osteoproliferative phenotype generating excessive bone formation that can result in joint fusion. The underlying mechanisms of this progression are poorly understood. Recent work has suggested that changes in Wnt signalling, a key bone regulatory pathway, may contribute to joint ankylosis in AS. Using the proteoglycan-induced spondylitis (PGISp) mouse model which displays spondylitis and eventual joint fusion following an initial inflammatory stimulus, we have characterised the structural and molecular changes that underlie disease progression.

Methods

PGISp mice were characterised 12 weeks after initiation of inflammation using histology, immunohistochemistry (IHC) and expression profiling.

Results

Inflammation initiated at the periphery of the intervertebral discs progressing to disc destruction followed by massively excessive cartilage and bone matrix formation, as demonstrated by toluidine blue staining and IHC for collagen type I and osteocalcin, leading to syndesmophyte formation. Expression levels of DKK1 and SOST, Wnt signalling inhibitors highly expressed in joints, were reduced by 49% and 63% respectively in the spine PGISp compared with control mice (P < 0.05) with SOST inhibition confirmed by IHC. Microarray profiling showed genes involved in inflammation and immune-regulation were altered. Further, a number of genes specifically involved in bone regulation including other members of the Wnt pathway were also dysregulated.

Conclusions

This study implicates the Wnt pathway as a likely mediator of the mechanism by which inflammation induces bony ankylosis in spondyloarthritis, raising the potential that therapies targeting this pathway may be effective in preventing this process.     

Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features

Demonstration of an association between inflammation and spinal ankylosis has been challenging. Until the advent of MRI, prospective study was not possible due to inaccessibility of tissue. Recent studies using MRI have described an association between the presence of bone edema at vertebral corners on MRI and the subsequent development of syndesmophytes at the corresponding vertebral corners on radiography. Although reports have also highlighted the development of new syndesmophytes where the baseline MRI shows no inflammation, MRI has limited sensitivity for detection of spinal inflammation that is clearly evident on histopathology. There are also crucial methodological challenges because radiographic assessment is limited to the anterior corners of the cervical and lumbar spine while MRI lesions in the cervical spine are often small while spurious inflammatory signal is common in the lumbar spine. Follow-up MRI evaluation in two independent studies has also shown that inflammatory lesions that resolve after anti-TNF therapy are more prone to develop into syndesmophytes. It may be possible that very early inflammatory lesions resolve completely without sequelae if anti-TNF therapy is introduced before new bone formation becomes largely autonomous. For an individual patient the overall development of new bone during anti-TNF therapy may therefore depend on the balance between the number of early and more mature inflammatory lesions. Clinical trials of anti-TNF agents in early spondyloarthritis together with prospective MRI studies will allow more detailed testing of this hypothesis as a major priority for the research agenda in spondyloarthritis.     

MRI and X-ray in axial spondyloarthritis: the relationship between inflammatory and structural changes

Demonstration of an association between inflammation and spinal ankylosis has been challenging. Until the advent of MRI, prospective study was not possible due to inaccessibility of tissue. Recent studies using MRI have described an association between the presence of bone edema at vertebral corners on MRI and the subsequent development of syndesmophytes at the corresponding vertebral corners on radiography. Although reports have also highlighted the development of new syndesmophytes where the baseline MRI shows no inflammation, MRI has limited sensitivity for detection of spinal inflammation that is clearly evident on histopathology. There are also crucial methodological challenges because radiographic assessment is limited to the anterior corners of the cervical and lumbar spine while MRI lesions in the cervical spine are often small while spurious inflammatory signal is common in the lumbar spine. Follow-up MRI evaluation in two independent studies has also shown that inflammatory lesions that resolve after anti-TNF therapy are more prone to develop into syndesmophytes. It may be possible that very early inflammatory lesions resolve completely without sequelae if anti-TNF therapy is introduced before new bone formation becomes largely autonomous. For an individual patient the overall development of new bone during anti-TNF therapy may therefore depend on the balance between the number of early and more mature inflammatory lesions. Clinical trials of anti-TNF agents in early spondyloarthritis together with prospective MRI studies will allow more detailed testing of this hypothesis as a major priority for the research agenda in spondyloarthritis.     

Assessment of the relationship between hyperalgesia and peripheral inflammation in magnesium-deficient rats

Magnesium-deficient rats develop simultaneously a significant lowering of nociceptive threshold and a generalized inflammation. We investigated the relationship between these two phenomena by testing drugs that are able to suppress the inflammation in this model. In weaning rats fed a magnesium-depleted diet for ten days, the nociceptive threshold was assessed by the paw pressure test and the inflammation by a clinical score. A non-steroidal anti-inflammatory drug (piroxicam); antagonists of H1 and H2 receptors (astemizole and cimetidine. respectively); a glucocorticoid (dexamethasone); an inhibitor of mastocyte degranulation (cromoglycate); and estradiol benzoate were used to block the inflammatory response. Dexamethasone and estradiol significantly suppressed the inflammation (p < 0.001 vs control group). Cromoglycate showed a delayed anti-inflammatory effect (p < 0.01 vs control group on D10). The combination of astemizole and cimetidine partially blocked the inflammation process, whereas astemizole and piroxicam were without effect. Regardless of the effect of the test drugs on inflammation, no change in the time course of hyperalgesia was observed. These data support the view that hyperalgesia induced by the magnesium-depleted diet is not a consequence of the inflammatory process.     

Age changes in the pubic symphysis of Macaca mulatta.

Age changes in the pubic symphyses of 142 Cayo Santiago rhesus monkeys (known age, sex and maternal genealogy) are described. Symphyseal development is sexually dimorphic. Males generate a ridge and furrow system which is gradually replaced by a solid ankylosis at the mid-sagittal plane. Female development parallels that of the male until puberty. With pregnancy and delivery, relaxation and reaggregation of pelvic ligaments binding the symphysis destroy the symphyseal face. Continued bearing of offspring inhibits mid-sagittal ankylosis. Limited estimates of skeletal age can be made by using symphyseal development as an indicator of senescence.     

Bone morphogenetic proteins in destructive and remodeling arthritis

Joint destruction and tissue responses determine the outcome of chronic arthritis. Joint inflammation and damage are often the dominant clinical presentation. However, in some arthritic diseases, in particular the spondyloarthritides, joint remodeling is a prominent feature, with new cartilage and bone formation leading to ankylosis and contributing to loss of function. A role for bone morphogenetic proteins in joint remodeling has been demonstrated in the formation of both enthesophytes and osteophytes. Data from genetic models support a role for bone morphogenetic protein signaling in cartilage homeostasis. Finally, this signaling pathway is likely to play a steering role in the synovium.     

Mandibular distraction in temporomandibular joint ankylosis

Condylar damage during childhood can produce ankylosis and alteration of the mandibular growth. In case of unilateral ankylosis occurring in early childhood, a mandibular hypoplasia of the affected side may develop. The patients have limitation of mouth opening, facial asymmetry, and chin deviation toward the affected side. The aims of this study are to show the use of distraction osteogenesis in mandibular hypoplasia associated with ankylosis and to present our experience with a new therapeutic option for the treatment of mandibular hypoplasia with unilateral ankylosis in the childhood consisting of the association of arthroplasty to treat the ankylosis and mandibular distraction to correct the facial asymmetry, both accomplished in the same surgical procedure. From November of 1996 to November of 1997, three male patients aged 2, 7, and 13 years with mandibular hypoplasia and ankylosis were treated by distraction osteogenesis. An arthroplasty consisting of the resection of the ankylotic block and interposition of a temporalis muscle flap, plus coronoidectomy was done in two of them and mandibular distraction was done in all three patients. Articular functional rehabilitation began on the first postoperative day. Mandibular distraction began on the fifth postoperative day with a rate of 1 mm per day, ending when the facial symmetry was achieved. From the first postoperative day, an increase in the mouth opening was achieved; this increase continued until ending the distraction. The average duration of distraction was 22 days. Average duration of consolidation was 6 weeks. Oral opening increased from 10 mm to 35 mm in the 7-year-old patient, from 9 mm to 27 mm in the 2-year-old patient, and from 14 mm to 38 mm in the 13-year-old patient. To date, oral opening and facial symmetry persist. Osseous mandibular distraction together with arthroplasty offers an excellent new alternative for treatment of patients with mandibular hypoplasia and associated ankylosis, with minimal morbidity and complications.     

Osteoimmunology and osteoporosis

The concept of osteoimmunology is based on growing insight into the links between the immune system and bone at the anatomical, vascular, cellular, and molecular levels. In both rheumatoid arthritis (RA) and ankylosing spondylitis (AS), bone is a target of inflammation. Activated immune cells at sites of inflammation produce a wide spectrum of cytokines in favor of increased bone resorption in RA and AS, resulting in bone erosions, osteitis, and peri-inflammatory and systemic bone loss. Peri-inflammatory bone formation is impaired in RA, resulting in non-healing of erosions, and this allows a local vicious circle of inflammation between synovitis, osteitis, and local bone loss. In contrast, peri-inflammatory bone formation is increased in AS, resulting in healing of erosions, ossifying enthesitis, and potential ankylosis of sacroiliac joints and intervertebral connections, and this changes the biomechanical competence of the spine. These changes in bone remodeling and structure contribute to the increased risk of vertebral fractures (in RA and AS) and non-vertebral fractures (in RA), and this risk is related to severity of disease and is independent of and superimposed on background fracture risk. Identifying patients who have RA and AS and are at high fracture risk and considering fracture prevention are, therefore, advocated in guidelines. Local peri-inflammatory bone loss and osteitis occur early and precede and predict erosive bone destruction in RA and AS and syndesmophytes in AS, which can occur despite clinically detectable inflammation (the so-called 'disconnection'). With the availability of new techniques to evaluate peri-inflammatory bone loss, osteitis, and erosions, peri-inflammatory bone changes are an exciting field for further research in the context of osteoimmunology.     

Is the Neutrophil-to-Lymphocyte Ratio an Exceptional Indicator for Metabolic Syndrome Disease and Outcomes?

ObjectivesTo show that there is relation between neutrophil-to-lymphocyte ratio (NLR) and metabolic syndrome and also, its components.FindingsMetabolic syndrome is associated with elevated fasting blood glucose, increased blood pressure, central obesity, decreased high-density lipoprotein, and increased triglyceride levels. Because of its growing incidence and prevalence and the effect that it has on developing other noncommunicable diseases, the importance gets even more value. The prediction and control of this disease in its early stages and in the most inexpensive way is of crucial need. Due to the role of chronic low-grade inflammation in metabolic syndrome, cytokines and inflammatory factors (like interleukin-6 and tumor necrosis factor-α) play a critical role on this phenomenon. The NLR is an inflammatory marker that has an unchallenging availability and has a reasonable cost. The NLR is related to obesity, type 2 diabetes, hypertension, and blood cholesterol levels.ConclusionThis suggests that there may be a relationship between the NLR and metabolic syndrome. The NLR, as a low-grade inflammation marker, indicates a positive relationship with central obesity. Also, studies indicate that the incidence of diabetes, its severity, and its control are related to the NLR. Hypertension and hyperlipidemia can both be noticed with higher NLRs. This rapid review assesses the association between metabolic syndrome and the NLR.     

Systemic inflammation and mortality in chronic obstructive pulmonary disease

Cardiovascular diseases and cancer (especially lung cancer) are leading causes of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Some have implicated systemic inflammation, which is commonly observed in COPD, as the potential mechanistic bridge between COPD and these disorders. This concept has been supported by animal studies especially in rabbits, which have clearly demonstrated the effect of local lung inflammation on systemic inflammation and on the progression of atherosclerosis and by cross-sectional population-based studies, which have shown a significant relationship between systemic inflammation, as measured by circulating C-reactive protein (CRP) and the risk of cardiovascular diseases in COPD patients. These data have been further extended by a recent study that has elucidated the temporal nature of the relationship between systemic inflammation and the risk of cardiovascular events and cancer in COPD patients. This study showed that baseline CRP levels predicted the incidence of cardiovascular events and cancer-specific mortality over 7 to 8 years of follow-up. CRP levels also predicted all-cause mortality. Collectively, these data indicate that systemic inflammation may play an important role in mediating the extra-pulmonary complications of COPD. Systemic inflammation may contribute substantially to the overall morbidity and mortality of COPD patients.     

Prostate inflammation and its potential impact on prostate cancer: a current review

Recent studies have identified a role for inflammation in the development and progression of several cancers, such as liver, stomach and the large intestine. Data from several studies has shown correlations between soluble inflammatory mediators, such as cytokines, chemokines and growth factors. However, a direct relationship between inflammation and prostate cancer has yet to be identified. Two major hurdles currently exist which limit the study of this relationship are first that animal models available for studying prostate inflammation are limited, and secondly that relatively little is known about the inflammatory response in the prostate. Here we first review the data demonstrating a correlation between inflammation and prostate cancer as well as review what is currently known about the inflammatory response in the prostate and the impact this inflammation has on the prostate tissue.     

Human eosinophils: Apoptosis versus survival in the mediation of inflammation

Eosinophil-derived mediators are thought to make a major contribution to the inflammation underlying a number of allergic diseases, most notably asthma. The toxic potential of eosinophils at tissue sites of inflammation might be limited if they were cleared by the process of programmed cell death or apoptosis. In this review we have examined the relationship between the signal transduction pathways important in controlling cytokine-induced prolonged survival and the mechanisms responsible for the induction and control of apoptosis in the eosinophil. A greater understanding of these processes might result in the development of novel therapeutic agents which would promote the safe and rapid removal by apoptosis of this important pro-inflammatory cell.     

Decreased expression of uteroglobin-related protein 1 in inflamed mouse airways is mediated by IL-9

Uteroglobin-related protein 1 (UGRP1) is a secretory protein, highly expressed in epithelial cells of airways. Although an involvement of UGRP1 in the pathogenesis of asthma has been suggested, its function in airways remains unclear. In the present study, a relationship between airway inflammation, UGRP1 expression, and interleukin-9 (IL-9), an asthma candidate gene, was evaluated by using a murine model of allergic bronchial asthma. A severe airway inflammation accompanied by airway eosinophilia and elevation of IL-9 in bronchoalveolar lavage (BAL) fluids was observed after ovalbumin (OVA) challenge to OVA-sensitized mice. In this animal model of airway inflammation, lung Ugrp1 mRNA expression was greatly decreased compared with control mice. A significant inverse correlation between lung Ugrp1 mRNA levels and IL-9 levels in BAL fluid was demonstrated by regression analysis (r = 0.616, P = 0.023). Immunohistochemical analysis revealed a distinct localization of UGRP1 in airway epithelial cells of control mice, whereas UGRP1 staining was patchy and faint in inflamed airways. Intranasal administration of IL-9 to naive mice decreased the level of Ugrp1 expression in lungs. These findings suggest that UGRP1 is downregulated in inflamed airways, such as allergic asthmatics, and IL-9 might be an important mediator for modulating UGRP1 expression.     

Low Vitamin D Status Is Associated with Systemic and Gastrointestinal Inflammation in Dogs with a Chronic Enteropathy

Introduction

Vitamin D deficiency, as assessed by serum concentrations of 25 hydroxyvitamin D (25(OH)D), has been linked to the development of over-zealous and inappropriate inflammation in humans. However, the relationship between vitamin D status and inflammation in dogs is ill-defined. Chronic enteropathies (CE) are frequently diagnosed in client owned dogs, have a wide range of serum 25(OH)D concentrations, and represent a spontaneous model in which to probe the relationship between vitamin D and inflammation. The hypothesis of this study was that vitamin D status would be negatively associated with systemic and gastrointestinal inflammation in dogs with a CE. The aim of this study was to examine the relationship between serum 25(OH)D concentrations and markers of systemic and gastrointestinal inflammation in a cohort of dogs with CE.

Methods and Materials

Serum 25(OH)D concentrations, together with neutrophil, monocyte, eosinophil and lymphocyte counts, duodenal histopathology scores, serum IL-2, IL-6, IL-8 and TNFα concentrations and were measured in 39 dogs with histologically confirmed CE. A linear regression model examined the relationship between serum 25(OH)D status and measures of inflammation.

Results

Serum 25(OH)D concentrations were negatively associated with neutrophil and monocyte counts, duodenal histopathology scores and serum IL-2 and IL-8 concentrations. Dogs with low serum 25(OH)D concentrations typically had an inflammatory signature characterised by high monocyte and neutrophil numbers together with low lymphocyte numbers. There is a need to establish whether low vitamin D status is a cause or consequence of inflammation.     

肥胖与慢性炎症

肥胖及其相关的代谢类疾病严重影响人类的健康,而肥胖诱导的慢性炎症是胰岛素抵抗和代谢综合症发病的关键因素.脂肪组织慢性炎症发生的机制及其与代谢综合症的关系已经成为全球瞩目的研究热点.慢性炎症的特征主要包括脂肪组织中促炎细胞因子表达量增加,抗炎细胞因子表达量降低以及大量巨噬细胞浸润.鉴于肥胖及其相关代谢综合症对人类健康的巨大危害,现对慢性炎症的发生机制,肥胖和慢性炎症之间的关系,脂肪组织炎症中巨噬细胞浸润以及和信号传导通路进行综述.     

Inflammation and Cognition in Older Adults: Evidence from Taiwan

Inflammation has been linked to clinical cognitive impairment, including Alzheimer’s disease. Less is known, however, about the relationship between inflammation and normal, age-associated cognitive decline. An understanding of the determinants of all types of cognitive decline is important for improving quality of life in an aging world. This study investigated whether biomarkers of inflammation were associated with cognitive function and decline in older Taiwanese adults. Data were from the Taiwan Longitudinal Study of Aging and the Social Environment and Biomarkers of Aging Study. Inflammation was measured in 2000 and 2006 as C-reactive protein, interleukin-6, soluble e-selectin, soluble intercellular adhesion molecule-1, and white blood cell count. Cognition was assessed by 10 cognitive and memory tasks, measured in 2006, 2007, and 2011. Growth curve models were used to examine the relationship between inflammation and cognitive score over this time period. Higher levels of inflammation were associated with lower baseline cognitive scores, but not with longitudinal change in cognitive score. This study did not support a causal link between inflammation and cognitive decline among this older cohort. The observed cross-sectional relationship could reflect a causal relationship that arises earlier in life, or confounding; additional research across the life course is warranted.     

Analysis of lacI mutations in Big Blue transgenic mice subjected to parasite-induced inflammation.

Parasite infections have long been associated with specific types of human cancers. Schistosoma hematobium is an inducer of urinary bladder cancer, Helicobacter pylori is a gastric carcinogen, and hepatitis B virus and Opisthorchis viverrini are causative agents of hepatocellular carcinoma. Another liver fluke, Fasciola hepatica, has also been identified as a neoplastic risk agent, primarily in animals. We used F. hepatica-induced inflammation in mice to determine if the presence of an aggressive liver fluke could induce mutagenic events in mammalian tissue. This provides a perspective on the relationship between chronic inflammation and cancer and may be a model for future studies on this complex association. In previous studies using the Big Blue^® transgenic mouse assay, we demonstrated an increase in lacI mutations in liver cells harvested from mice harboring F. hepatica flukes when compared to uninfected control animals. In these studies, we report on the types of mutations associated with this parasite infection. The observed mutational spectrum roughly corresponded to the spectrum of spontaneous mutations in liver cells when compared to control (uninfected) animals. However, the spectrum of mutations from parasitized animals showed a significant increase in complex changes and multiple mutations (18.2%) when compared to what would be expected from control animals (2.8%).