Copper Chelation Represses the Vascular Response to Injury

The induction of an acute inflammatory response followed by the release of polypeptide cytokines and growth factors from peripheral blood monocytes has been implicated in mediating the response to vascular injury. Because the Cu2+-binding proteins IL-1alpha and fibroblast growth factor 1 are exported into the extracellular compartment in a stress-dependent manner by using intracellular Cu2+ to facilitate the formation of S100A13 heterotetrameric complexes and these signal peptideless polypeptides have been implicated as regulators of vascular injury in vivo, we examined the ability of Cu2+ chelation to repress neointimal thickening in response to injury. We observed that the oral administration of the Cu2+ chelator tetrathiomolybdate was able to reduce neointimal thickening after balloon injury in the rat. Interestingly, although immunohistochemical analysis of control neointimal sections exhibited prominent staining for MAC1, IL-1alpha, S100A13, and the acidic phospholipid phosphatidylserine, similar sections obtained from tetrathiomolybdate-treated animals did not. Further, adenoviral gene transfer of the IL-1 receptor antagonist during vascular injury also significantly reduced the area of neointimal thickening. Our data suggest that intracellular copper may be involved in mediating the response to injury in vivo by its ability to regulate the stress-induced release of IL-1alpha by using the nonclassical export mechanism employed by human peripheral blood mononuclear cells in vitro

CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis

The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity. These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease. In this review, we focus on CCN3, a founding member of this family, and its role in regulating cells within the bone microenvironment. CCN3 impairs normal osteoblast differentiation through multiple mechanisms, which include the neutralization of pro-osteoblastogenic stimuli such as BMP and Wnt family signals or the activation of pathways that suppress osteoblastogenesis, such as Notch. In contrast, CCN3 is known to promote chondrocyte differentiation. Given these functions, it is not surprising that CCN3 has been implicated in the progression of primary bone cancers such as osteosarcoma, Ewing’s sarcoma and chondrosarcoma. More recently, emerging evidence suggests that CCN3 may also influence the ability of metastatic cancers to colonize and grow in bone

AB0815 FIRST DEGREE RELATIVES OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS - CLINICAL, SEROLOGICAL AND IMMUNOLOGICAL CORRELATIONS

Background:Antinuclear antibodies (ANA) have been unequivocally recognized as essential for diagnosis and play both pathogenic and diagnostic roles in systemic lupus erythematosus (SLE). SLE and ANA have also been found to be more often among relatives of SLE patients. ANA and other immunological changes are known to appear prior to the clinical onset of the disease and thus can be used as predictors. Studies have reported that relatives of SLE patients who later transitioned to SLE displayed more lupus-associated autoantibody specificities and had early clinical signs. They also displayed elevated baseline plasma levels of inflammatory mediators, including B-lymphocyte stimulator (BLyS) and interferon-associated chemokines, with concurrent decreases in levels of regulatory mediators, e.g. tumor growth factor (TGF)-β. Commonly recognized risk factors for SLE are signs of past Epstein-Barr (EBV) infection, use of estrogen drugs and current smoking. It seems that ANA, immunologic changes and risk factors have not been investigated together in relatives of SLE patients.Objectives:The aim of the study was to determine the relative prevalence of clinical signs of SLE or connective tissue disease (CTD), smoking, use of estrogen drugs and levels of circulating ANA, BLyS, IFN-α, TGF-β, anti-EBV viral capsid antigen (VCA) IgM and IgG antibodies among sera of FDR, non-FDR healthy individuals and SLE patients.Methods:Forty three FDRs of SLE patients were studied along with 15 SLE patients and 15 clinically healthy subjects as control groups. The FDRs and the healthy answered a questionnaire about early clinical signs of CTD, smoking and estrogen use history. The questionnaire was developed based on the existing Screening Questionnaire for Connective Tissue Diseases and current knowledge of most early signs of CTD. Blood samples were obtained and tested for ANA, both by indirect immunofluorescence and immunoblot, anti-dsDNA by ELISA. ELISA was also performed to measure levels of BLys, IFN-α, TGF-β, anti-EBV IgM and IgG.Results:More than half of the FDRs displayed ANA in titer 1:160 or more, with predominately AC-4 type of fluorescence according to International Classification on ANA Patterns (ICAP) compared to only AC-1 and AC-0 among patients and controls respectively. A correlation between the ANA titer and the number of complaints was found. This was particularly valid or reported skin complaints and oral ulcers which appeared more frequently when ANA was 1:320 or above (p=0,018 and 0,038 respectively). Furthermore, oral ulcerations showed positive correlation with the presence of anti-Ro60. No associations were found in the healthy group between reported complaints and ANA titers. Smoking and estrogen use did not differ across the three groups. Patients showed significant differences in levels of BLys (p=0,027), TGF-β (p=0,019) and anti-EBV IgG (p=0.041) compared to both FDRs and controls. Without reaching statistical significance, levels of TGF-β tend to split the FDR group into “healthy-like” and “SLE-like”.Conclusion:Our results show that FDR ANA levels are between those of SLE patients and healthy subject groups. This is consistent with previous studies. The data also suggest that ANA positivity correlates with reported complaints, some of which could be interpreted as very early clinical signs of SLE. Of note, anti-Ro60 is known to be among the earliest ANA that appear in “future” SLE patients and in this study they are related to oral complaints that could be caused by early sicca phenomena. Immunologically, our data support previous findings [1] that the FDRs are a heterogenic group with different “lupus-developing” potential.References:[1]Munroe МE. et al, Soluble Mediators and Clinical Features Discern Risk of Transitioning to Classified Disease in Relatives of Systemic Lupus Erythematosus Patients, Arthritis Rheumatol. 2017 March; 69(3): 630–642.Disclosure of Interests:Bogdan Penev: None declared, Georgi Vasilev: None declared, Dobroslav Kyurkchiev: None declared, Simeon Monov Speakers bureau: I have been paid for giving lectures on statistical data on efficacy of many pharmaceutical products on various companies</jats:sec