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

Extraintestinal Manifestations and Intestinal Complications in Patients with Crohn's Disease: Associations with Some Clinico-Laboratory Findings, Immunological Markers and Therapy

Crohn's disease (CD) may have some severe complications that pose an increasing health burden and negatively impact the quality of life. There are two major types - intestinal and extraintestinal complications, in which immune and non-immune mechanisms take place. We aimed to search for some associations between specific extraintestinal manifestation and intestinal complications in CD patients with some clinicallaboratory findings, immunological markers, and the therapy administered. We examined retrospectively medical files of 26 patients with CD at mean age 42 ± 13 years, including the laboratory results. The immunological markers fecal calprotectin (FC) and fecal lactoferrin (FL) were assessed in frozen fecal samples of the chosen patients. Seventy-three percent of the investigated CD patients had some extraintestinal manifestation and/or intestinal complications, at least 13/26 had intestinal complications. All three patients with extraintestinal signs were positive for FC and 2/3 were positive for FL. We observed a higher serum level of CRP (24.49 mg/l vs. 3.13 mg/l, p = 0.010), slightly lowered serum level of hemoglobin (120 g/l vs. 145 g/l, p = 0.044) and about 2-fold lower iron level (7.23 μmol/l vs. 14.0 μmol/l, p = 0.019) in patients with intestinal complications compared to patients without complications, respectively. Four out of thirteen patients with intestinal complications were without immunosuppressive therapy at the time of our study, and nine out of thirteen - on immunosuppressive drugs. Routine laboratory and immunology testing could be beneficial for gastroenterologists in identifying patients at high risk for the development of complications and in the decision making for more aggressive therapy early after diagnosis