Human Full-Length Osteoprotegerin Induces the Proliferation of Rodent Vascular Smooth Muscle Cells both in vitro and in vivo

Abstract

Background/Aims: Since elevated plasma levels of osteoprotegerin (OPG) represent a risk factor for death and heart failure in patients affected by diabetes mellitus and coronary artery disease, this study aimed to elucidate potential roles of OPG in the pathogenesis of atherosclerosis. Methods and Results: Recombinant human full-length OPG, used at concentrations comparable to the elevated levels found in the serum of diabetic patients, significantly increased the proliferation rate of rodent vascular smooth muscle cells (VSMC). To mimic the moderate chronic elevation of OPG observed in diabetic patients, low doses (1 µg/mouse) of full-length human OPG were injected intraperitoneally every 3 weeks in diabetic apolipoprotein E (apoE)-null mice. The group of animals treated for 12 weeks with recombinant OPG showed a small increase in the total aortic plaque area at necropsy in comparison to vehicle-treated animals. Importantly, while no differences in the amount of interstitial collagen or the degree of macrophage infiltration were observed between OPG-treated and vehicle-treated apoE-null diabetic animals, a significant increase in the number of α-actin-positive smooth muscle cells was observed in the plaques of OPG-treated mice. Conclusions: Our data suggest that OPG promotes VSMC proliferation and might be directly involved in pathogenetic aspects of atherosclerosis.

Multimarker Risk Assessment Including Osteoprotegerin and CXCL16 in Acute Coronary Syndromes

“…30 The inverse relationship between OPG and LVEF in our material is, therefore, not surprising, and we have also previously 31 noted a relationship between OPG and infarct markers and BNP. Enhanced myocardial expression of CXCL16 has been demonstrated in both experimental and clinical HF, 17 promoting muscle regeneration.…”

No influence of OPG and its ligands, RANKL and TRAIL, on proliferation and regulation of the calcification process in primary human vascular smooth muscle cells

“…we did not find direct effects of OPG or its ligands, RANKL or TRAIL, on either proliferation, gene expression pattern of calcification-associated genes, or the development of calcification in HVSMCs.siRNA-mediated knockdown of OPG in HVSMCs had no effects on either determination of total number of cells/well, [ 3 H]-thymidine incorporation, or total protein/well. Other investigators have, however, found that OPG either stimulated or inhibited proliferation of VSMCs (Candido et al, 2009;Corallini et al, 2009;Moran et al, 2005;Ovchinnikova et al, 2009). Importantly, in these previously published experiments, recombinant OPG was added to VSMCs in concentrations that are comparable to levels which the cells can produce within a short period (Olesen et al, 2005).…”

“…Reports of direct effects of the OPG-RANKL-TRAIL system on HVSMCs are, however, contradictory. Three independent in vitro studies, based on the addition of OPG, found that this molecule stimulates proliferation of VSMCs (Candido et al, 2009;Corallini et al, 2009;Ovchinnikova et al, 2009). On the contrary, Moran et al showed that OPG impaired proliferation (Moran et al, 2005).…”

Osteoprotegerin promotes the proliferation of chondrocytes and affects the expression of ADAMTS-5 and TIMP-4 through MEK/ERK signaling

“…ERK1/2 and P38MAPK pathways have been confirmed to be involved in the cell proliferation and differentiation of chondrocytes (27)(28)(29). It was demonstrated that soluble OPG activated several signals in different cell types, inducing cytoskeleton reorganization through FAK, Src and ERK1/2 signaling in endothelial cells (1), promoting endothelial cell proliferation and migration partly via ERK1/2 signaling (30), increasing periodontal ligament cells expressing osteopontin via syndecan-1 and PI3k/AKT (9), altering the morphology and function of pancreatic islets possibly via the renin-angio-tensin system (31) and inducing proliferation of rodent vascular smooth muscle cells (32). In the present study, MAPK signaling molecules were analyzed as candidate downstream effectors of OPG.…”