TWEAK and Fn14 expression in the pathogenesis of joint inflammation and bone erosion in rheumatoid arthritis

Extent: 10p.INTRODUCTION: TNF-like weak inducer of apoptosis (TWEAK) has been proposed as a mediator of inflammation and bone erosion in rheumatoid arthritis (RA). This study aimed to investigate TWEAK and TWEAK receptor (Fn14) expression in synovial tissue from patients with active and inactive rheumatoid arthritis (RA), osteoarthritis (OA) and normal controls and assess soluble (s)TWEAK levels in the synovial fluids from patients with active RA and OA. Effects of sTWEAK on osteoclasts and osteoblasts were investigated in vitro. METHODS: TWEAK and Fn14 expression were detected in synovial tissues by immunohistochemistry (IHC). Selected tissues were dual labelled with antibodies specific for TWEAK and lineage-selective cell surface markers CD68, Tryptase G, CD22 and CD38. TWEAK mRNA expression was examined in human peripheral blood mononuclear cells (PBMC) sorted on the basis of their expression of CD22. sTWEAK was detected in synovial fluid from OA and RA patients by ELISA. The effect of sTWEAK on PBMC and RAW 264.7 osteoclastogenesis was examined. The effect of sTWEAK on cell surface receptor activator of NF Kappa B Ligand (RANKL) expression by human osteoblasts was determined by flow cytometry. RESULTS: TWEAK and Fn14 expression were significantly higher in synovial tissue from all patient groups compared to the synovial tissue from control subjects (P < 0.05). TWEAK was significantly higher in active compared with inactive RA tissues (P < 0.05). TWEAK expression co-localised with a subset of CD38+ plasma cells and with CD22+ B-lymphocytes in RA tissues. Abundant TWEAK mRNA expression was detected in normal human CD22+ B cells. Higher levels of sTWEAK were observed in synovial fluids isolated from active RA compared with OA patients. sTWEAK did not stimulate osteoclast formation directly from PBMC, however, sTWEAK induced the surface expression of RANKL by human immature, STRO-1+ osteoblasts. CONCLUSIONS: The expression of TWEAK by CD22+ B cells and CD38+ plasma cells in RA synovium represents a novel potential pathogenic pathway. High levels of sTWEAK in active RA synovial fluid and of TWEAK and Fn14 in active RA tissue, together with the effect of TWEAK to induce osteoblastic RANKL expression, is consistent with TWEAK/Fn14 signalling being important in the pathogenesis of inflammation and bone erosion in RA.Anak A. S. S. K. Dharmapatni, Malcolm D. Smith, Tania N. Crotti, Christopher A. Holding, Cristina Vincent, Helen M. Weedon, Andrew C. W. Zannettino, Timothy S. Zheng, David M. Findlay, Gerald J. Atkins and David R. Hayne

Scleroderma in South Australia: epidemiological observations of possible pathogenic significance.

BACKGROUND: Scleroderma is an autoimmune disorder of unknown cause. Previous epidemiological studies have suggested some regional clustering and associations with occupations involving exposure to silica dusts and hydrocarbons. AIMS: To determine: (i) prevalence and incidence of scleroderma in South Australia (SA), a state with a stable population living in well-defined urban, rural and industrial regions, (ii) hospital separation rates, (iii) cumulative survival rates, (iv) gender and disease subclassification, (v) geographical residency and occupations, (vi) familial associations and (vii) age at onset versus age-specific incidence rate. METHODS: Creation of the South Australian Scleroderma Register (SASR) to identify demographics and clinical and serological features of all scleroderma patients resident in SA. RESULTS: Scleroderma occurs in South Australia with a point prevalence of 23 per 10(5) and an incidence of approximately 1/15th of this. However, this prevalence is high compared with other regional world studies. Scleroderma is predominantly a female disease, with most patients having the limited form of scleroderma characterized by the presence of the anticentromere antibody and a mean survival of 27.6 years. In contrast, diffuse scleroderma is a less benign disease occurring at an early age of onset and has a mean survival of 9.6 years. Scleroderma occurs throughout SA without regional localization. Weak associations are seen in males, but not females, with occupations involving possible environmental exposure to silica or hydrocarbons. Scleroderma rarely occurs in families. CONCLUSION: No strong genetic or environmental influences were found to account for the relatively common occurrence of scleroderma in SA. The age at onset versus age-specific incidence curve suggests that scleroderma can be considered as a stochastic illness involving a number of random events occurring in a predisposed population. These random events may involve mutations of pivotal somatic genes

The physiological role of endoglin in the cardiovascular system

Endoglin (CD105) is an integral membrane glycoprotein that serves as a coreceptor for members of the transforming growth factor-β superfamily of proteins. A major role for endoglin in regulating transforming growth factor-β-dependent vascular remodeling and angiogenesis has been postulated based on the following: 1) endoglin is the gene mutated in hereditary hemorrhagic telangiectasia type 1, a disease characterized by vascular malformations; 2) endoglin knockout mice die at midgestation because of defective angiogenesis; 3) endoglin is overexpressed in neoangiogenic vessels, during inflammation, and in solid tumors; and 4) endoglin regulates the expression and activity of endothelial nitric oxide synthase, which is involved in angiogenesis and vascular tone. Besides the predominant form of the endoglin receptor (long endoglin isoform), two additional forms of endoglin have been recently reported to play a role in the vascular pathology and homeostasis: the alternatively spliced short endoglin isoform and a soluble endoglin form that is proteolytically cleaved from membrane-bound endoglin. The purpose of this review is to underline the role that the different forms of endoglin play in regulating angiogenesis, vascular remodeling, and vascular tone, as well as to analyze the molecular and cellular mechanisms supporting these effectsThis work was supported by Spanish Ministry of Science and Innovation Grants SAF2007-61827 (to C. Bernabeu) and SAF2007-63893 (to J. M. López-Novoa), Instituto de Salud Carlos III Grants ISCIII-CIBER CB/06/07/0038 (to C. Bernabeu) and ISCIII-RD06/0016 RedinRen (to J. M. López-Novoa), and Junta de Castilla y Leon Grant GR100 (to J. M. López-Novoa)Peer reviewe