Mesenchymal stem cells-derived vascular smooth muscle cells release abundant levels of osteoprotegerin.

Although several studies have shown that the serum levels of osteoprotegerin (OPG) are significantly elevated in patients affected with atherosclerotic lesions in coronary and peripheral arteries, the cellular source and the role of OPG in the physiopathology of atherosclerosis are not completely defined. Therefore, we aimed to investigate the potential contribution of mesenchymal stem cells in the production/release of OPG. OPG was detectable by immunohistochemistry in aortic and coronary atherosclerotic plaques, within or in proximity of intimal vascular smooth muscle cells (SMC). In addition, bone marrow mesenchymal stem cell (MSC)-derived vascular SMC as well as primary aortic SMC released in the culture supernatant significantly higher levels of OPG with respect to MSC-derived endothelial cells (EC) or primary aortic EC. On the other hand, in vitro exposure to full-length human recombinant OPG significantly increased the proliferation rate of aortic SMC cultures, as monitored by bromodeoxyuridine incorporation. Taken together, these data suggest that OPG acts as an autocrine/paracrine growth factor for vascular SMC, which might contribute to the progression of atherosclerotic lesions.

Mesenchymal stem cells-derived vascular smooth muscle cells release abundant levels of osteoprotegerin.

Although several studies have shown that the serum levels of osteoprotegerin (OPG) are significantly elevated in patients affected with atherosclerotic lesions in coronary and peripheral arteries, the cellular source and the role of OPG in the physiopathology of atherosclerosis are not completely defined. Therefore, we aimed to investigate the potential contribution of mesenchymal stem cells in the production/release of OPG. OPG was detectable by immunohistochemistry in aortic and coronary atherosclerotic plaques, within or in proximity of intimal vascular smooth muscle cells (SMC). In addition, bone marrow mesenchymal stem cell (MSC)-derived vascular SMC as well as primary aortic SMC released in the culture supernatant significantly higher levels of OPG with respect to MSC-derived endothelial cells (EC) or primary aortic EC. On the other hand, in vitro exposure to full-length human recombinant OPG significantly increased the proliferation rate of aortic SMC cultures, as monitored by bromodeoxyuridine incorporation. Taken together, these data suggest that OPG acts as an autocrine/paracrine growth factor for vascular SMC, which might contribute to the progression of atherosclerotic lesions.

Elevated levels of TRAIL in systemic lupus erythematosus are associated to the presence of anti-SSA/SSB antibodies.

The objective of this study was to determine potential relationship between the levels of serum TNF-related apoptosis inducing ligand (TRAIL) and osteoprotegerin (OPG) and clinical markers in systemic lupus erythematosus (SLE) patients. Forty SLE patients with inactive disease were enrolled in this study. For comparison, 20 Sjögren's syndrome (SS) patients and 30 normal controls were also analysed. Serum levels of TRAIL and OPG were determined by ELISA. Serum TRAIL and OPG concentrations in SLE patients were significantly (P < 0.05) higher than those in healthy volunteers. Of note, serum TRAIL but not OPG was significantly (P < 0.05) higher in the SLE patient subset characterized by the presence of anti-SSA/SSB antibodies. The relationship between high levels of TRAIL and SSA/SSB antibodies was further supported by the analysis of SS patients characterized by SSA/SSB antibodies positivity, in which TRAIL levels resulted comparable to the subgroup of anti-SSA/SSB positive SLE patients. The presence of SSA/SSB antibodies, targeting a specific subset of SLE and SS patients, is related to increased serum levels of TRAIL but not of OPG.

TRAIL promotes the survival, migration and proliferation of vascular smooth muscle cells.

Human and rat primary sub-cultured vascular smooth muscle cells (VSMCs) showed clear expression of the death receptors TRAIL-R1 and TRAIL-R2; however, recombinant soluble TRAIL did not induce cell death when added to these cells. TRAIL tended to protect rat VSMCs from apoptosis induced either by inflammatory cytokines tumor necrosis factor-alpha + interleukin-1beta + interferon-gamma or by prolonged serum withdrawal, and promoted a significant increase in VSMC proliferation and migration. Of note, all the biological effects induced by TRAIL were significantly inhibited by pharmacological inhibitors of the ERK pathway. Western blot analysis consistently showed that TRAIL induced a significant activation of ERK1/2, and a much weaker phosphorylation of Akt, while it did not affect the p38/MAPK pathway. Taken together, these data strengthen the notion that the TRAIL/TRAIL-R system likely plays a role in the biology of the vascular system by affecting the survival, migration and proliferation of VSMCs.