Advanced bone formation in mice with a dominant-negative mutation in the thyroid hormone receptor β gene due to activation of Wnt/β-catenin signaling
by John Logan
Thyroid hormone (T3) acts in chondrocytes and bone-forming osteoblasts to control bone development and maintenance but... more Thyroid hormone (T3) acts in chondrocytes and bone-forming osteoblasts to control bone development and maintenance but the signaling pathways mediating these effects are poorly understood. ThrbPV/PV mice have a severely impaired pituitary-thyroid axis and elevated thyroid hormone levels due to a dominant-negative mutant T3-receptor (TRβPV) that cannot bind T3 and interferes with the actions of wild-type TR. ThrbPV/PV mice have accelerated skeletal development due to unknown mechanisms. We performed microarray studies in primary osteoblasts from wild-type mice and ThrbPV/PV mice. Activation of the canonical Wnt signaling in ThrbPV/PV mice was confirmed by in situ hybridization analysis of Wnt target gene expression in bone during post-natal growth. By contrast, T3 treatment inhibited Wnt signaling in osteoblastic cells, suggesting T3 inhibits the Wnt pathway by facilitating proteasomal degradation of β-catenin and preventing its accumulation in the nucleus. Activation of the Wnt pathway in ThrbPV/PV mice, however, results from a gain-of-function for TRβPV that stabilizes β-catenin despite the presence of increased thyroid hormone levels. These studies demonstrate novel interactions between T3 and Wnt signaling pathways in the regulation of skeletal development and bone formation.
Illness perceptions account for variation in positive outlook as well as psychological distress in Rheumatoid Arthritis
by Sam Norton
S. van Os, S. Norton, L. D. Hughes, & J. Chilcot (2011). Psychology, Health & Medicine, in press
Psychological distress in rheumatoid arthritis (RA) is associated with adverse clinical outcomes, and appears highly... more Psychological distress in rheumatoid arthritis (RA) is associated with adverse clinical outcomes, and appears highly related to patient’s illness perceptions. This study aimed to investigate the association between illness perceptions, psychological distress, positive outlook, and physical outcomes in RA. 230 patients aged > 18 years and prescribed at least one DMARD were recruited from outpatient clinics across Hertfordshire (England). Patients completed a questionnaire that assessed psychological distress and positive outlook (DAPOS), illness perceptions (IPQ-R), and functional disability (HAQ). Information regarding prescribed medication and disease activity (DAS28) was collected from medical notes. Psychological distress, but not positive outlook, was associated with functional disability and DAS28. After controlling for sex, age and DAS28, perceptions of greater symptomatology (identity) and lesser understanding of RA (coherence) were significantly associated with increased psychological distress. Perceptions of greater treatment control were associated with greater positive outlook, but only for those with low DAS28. Coherence was also associated with positive outlook. These findings indicate that illness perceptions may influence psychological distress and positive outlook in RA patients, and may therefore be a useful basis for future psychological interventions.
Hydrogen sulfide-releasing diclofenac derivatives inhibit breast cancer-induced osteoclastogenesis in vitro and prevent osteolysis ex vivo.
by John Logan
Published in British Journal of Pharmacology. This paper using model systems I designed.
Background and purpose: Hydrogen sulfide (H(2) S) and prostaglandins are both implicated in inflammation, cancer and... more Background and purpose: Hydrogen sulfide (H(2) S) and prostaglandins are both implicated in inflammation, cancer and bone turnover, and non-steroidal anti-inflammatory drugs (NSAIDs) and H(2) S donors exhibit anti-inflammatory and anti-tumour properties. H(2) S-releasing diclofenac (S-diclofenac) derivatives are a novel class of NSAIDs which combine the properties of a H(2) S donor with those of a conventional NSAID. Experimental approach: We studied the effects of the S-diclofenac derivatives ACS15 and ACS32 on osteoclast and osteoblast differentiation and activity in vitro, human and mouse breast cancer cells support for osteoclast formation and signalling in vitro, and osteolysis ex vivo. Key results: The S-diclofenac derivatives ACS15 and ACS32 inhibited the increase in osteoclast formation induced by human MDA-MB-231 and MCF-7 and mouse 4T1 breast cancer cells without affecting breast cancer cell viability. Conditioned media from human MDA-MB-231 cells enhanced IκB phosphorylation and osteoclast formation and these effects were significantly inhibited following treatment by ACS15 and ACS32, whereas the parent compound diclofenac had no effects. ACS15 and ACS32 inhibited RANKL-induced osteoclast formation and resorption, and caused caspase-3 activation and apoptosis in mature osteoclasts via a mechanism dependent on IKK/NFκB inhibition. In calvaria organ culture, human MDA-MB-231 cells caused osteolysis and this effect was completely prevented following treatment with ACS15 and ACS32. Conclusions and implications: S-diclofenac derivatives inhibit osteoclast formation and activity, suppress breast cancer cell support for osteoclastogenesis, and prevent osteolysis. This suggests that H(2) S-releasing diclofenac derivatives exhibit anti-resorptive properties which might be of clinical value in the treatment of osteolytic bone disease.
Primary Human CD4+ T cells have diverse levels of membrane lipid order that correlate with their function.
by Chrissie Lim
2nd Co-author: Miguel L, Owen DM, [Lim C], Liebig C, Evans J, Magee AI and Jury EC.
In press, the Journal of Immunology. (Accepted for publication, December 2010.)
Autoantibodies and Diagnosis of Rheumatoid Arthritis
by Tracy Rodman
Authors; Huizinga Tom WJ, Oswald J Erik
Published in Touch European Musculoskeletal Review, 2008;3(1):27-8
Sustained clinical remission in rheumatoid arthritis: prevalence and prognostic factors in an inception cohort of patients treated with conventional DMARDs
by Sam Norton
Jayakumar, K., Norton, S., Dixey, J., James, D., Gough, A., Williams, P., Prouse, P., Young, A. (2012). Rheumatology 51 (1): 169-175.
Objective: Clinical remission is now a realistic goal in managing rheumatoid arthritis (RA) following the introduction... more
Objective: Clinical remission is now a realistic goal in managing rheumatoid arthritis (RA) following the introduction of biologic agents. As there is limited data on sustained remission in conventionally treated RA, this study examines prevalence and predictive factors of sustained remission in a pre-biologic inception cohort of RA.
Methods: Patients with recent onset RA and prior to use of disease modifying anti rheumatic drugs (DMARDs) were recruited from nine centres. Standard clinical and radiological assessments were recorded at baseline and yearly. Point remission was defined by disease activity scores (DAS) of <1.6, and sustained remission if DAS was <1.6 at all 3, 4 and 5yr follow ups. Sustained remission was compared to baseline features and to mortality, and to radiological and functional progression in 704 patients.
Results: Point remission at 3, 4 and 5yrs was 25%, 26% and 22% respectively. 11% (n=78) had sustained remission. Male sex, short duration of symptoms and less tender joints at baseline were independent predictors of sustained remission. These patients had less DMARD therapies and less radiographic progression by 5yrs. Mean HAQ decreased from 0.79 to 0.13 (p<0.001) in sustained remission, compared to an increase from 0.92 to 1.1 (p<0.001) in the non-remission group.
Conclusion: Sustained clinical remission by 5yrs with conventional DMARDs was 11%, half as likely as point remission. Prognostic factors were similar to comparable studies and simple to measure. Patients in sustained clinical remission showed less structural damage and better functional outcomes.
Distinct psychological distress trajectories in rheumatoid arthritis: findings from an inception cohort
by Sam Norton
Norton, S., Sacker. A., Young, A., & Done, J. (2011). Journal of Psychosomatic Research, 71(5):290-295.
Objective: As with other chronic physical illness, rates of depressive disorder are high in rheumatoid arthritis (RA).... more
Objective: As with other chronic physical illness, rates of depressive disorder are high in rheumatoid arthritis (RA). The aim of the current study was to identify distinct trajectories of psychological distress over 10-years in a cohort of RA patients recruited very early in the course of the disease.
Methods: Psychological distress as measured by the Hospital Anxiety and Depression Scale total score was assessed annually in a subgroup of 784 patients enrolled in a multi-centre RA inception cohort (Early RA Study). A latent growth mixture modelling (GMM) approach was used to identify distinct psychological distress patterns.
Results: Four distinct psychological distress trajectories were observed: low-stable (68%), high-stable (12%), high-decreasing (9%) and low-increasing (11%). Symptoms of pain, stiffness and functional impairment were significantly associated with levels of psychological distress at the time of diagnosis and after 3-years; serological markers of disease activity (ESR and CRP) were not.
Conclusions: Although the majority of individuals developing RA experience little or no impact of the effects of the disease on their psychological well-being, a significant proportion experience high levels of distress at some point which may be related to their subjective appraisal of RA. Assessment and treatment of psychological distress should occur synchronously with somatic symptoms.
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Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort
by Sam Norton
Koduri, G., Norton, S., Young, A. et al. (2010). Rheumatology 49(8):1483-1489
Objectives. Pulmonary complications of RA are well described. Although some are benign, interstitial lung disease... more
Objectives. Pulmonary complications of RA are well described. Although some are benign, interstitial lung disease (ILD) has a poor prognosis. Few RA inception cohorts have reported the natural history of ILD related to RA (RA-ILD). We examine its incidence, outcome and prognostic indicators.
Methods. Extra-articular features and comorbidity have been recorded yearly in a well-established inception cohort of RA with a 20-year follow-up. Standard clinical, laboratory and radiological measures of RA were recorded at baseline and yearly. Details of deaths were provided by a national central register.
Results. Out of 1460 patients, 52 developed RA-ILD, half either at baseline or within 3 years of onset. The annualized incidence was 4.1/1000 (95% CI 3.0, 5.4) and the 15-year cumulative incidence 62.9/1000 (95% CI 43.0, 91.7). Incidence of RA-ILD was associated with older age, raised baseline ESR and HAQ. Evidence to implicate any drug effect (e.g. MTX) was lacking. Of these patients, 39 died, attributed to RA-ILD in 28. Median survival following diagnosis of RA-ILD was 3 years.
Conclusions. RA-ILD is an important and early feature of RA. It is related to disease activity and has a poor prognosis. Further studies are required to determine whether screening for pulmonary disease would identify these patients at an earlier stage.
Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis
by Sam Norton
Young, A., Koduri, G., Batley, M. et al. (2007). Rheumatology 46(2):350-357
Objective. To examine the cause of death in a large UK inception cohort of rheumatoid arthritis (RA), and whether this... more
Objective. To examine the cause of death in a large UK inception cohort of rheumatoid arthritis (RA), and whether this was related to disease duration and severity, treatment effects or extra-articular features and complications of RA.
Methods. Standard clinical, laboratory, radiological and socio-economic measures were recorded at baseline and yearly in an inception cohort started in nine centres in 1986. Date and the cause of death were based on death certificates and the comparisons made with age and sex matched population figures. Risk factors for mortality were identified from baseline measures of disease.
Results. There were 459 deaths (32%) in 1429 patients followed for up to 18 yrs. Standard mortality ratio was 1.27. Survival was significantly lower in the first 7 yrs of RA. Excess mortality was seen in cardiovascular disease (31%), pulmonary fibrosis (4%) and lymphoma (2.3%). Baseline predictors for mortality were men, older age, poor function, lower socio-economic status, extra-articular features, comorbidity, rheumatoid factor, X-ray erosions, high-ESR and low-haemoglobin.
Conclusion. There was a modest increase in mortality in RA, mainly in the first 7 yrs. Deaths from cardiovascular disease and pulmonary fibrosis were higher than expected, but treatment-related deaths were low. Risk factors included less favourable socio-economic status, markers of disease severity and diminished function within the first year.