osteoprotegerin and Hyperplasia

Skeletal resistance to parathyroid hormone (PTH) was suggested initially as a mechanism of PTH hypersecretion in uremia. Because of the effective suppression of PTH by recently developed therapeutic modalities, this background abnormality has been uncovered and currently recognized as relative hypoparathyroidism in terms of its relation to bone turnover. Thus, PTH levels two to three times greater than normal are usually required to keep bone turnover normal in uremia. Recent studies suggested that PTH activity may be overestimated using the conventional intact PTH assay. In addition, several steps to osteoclastogenesis are suspected to be disturbed in uremia. Additional studies at cellular and molecular levels are needed to establish preventive and therapeutic modalities for this abnormality.

Topics: Bone and Bones; Bone Resorption; Disease Progression; Glycoproteins; Humans; Hyperplasia; Osteoprotegerin; Parathyroid Glands; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Uremia

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are related to in-stent-restenosis (ISR) following percutaneous coronary intervention (PCI). Osteoprotegerin (OPG) has been implicated in various vascular diseases. However, the effects of OPG on ISR and the underlying mechanism remained elusive. We here investigated the association between OPG and ISR, and to demonstrate the role and potential mechanisms of OPG in neointimal hyperplasia.. From 2962 patients who received coronary angiography and follow-up coronary angiography at approximately one year, 291 patients were diagnosed with ISR, and another 291 gender- and age- matched patients without ISR were selected as controls. Serum OPG levels were significantly increased in patients with ISR. Multivariable logistic regression analysis indicated that OPG level was independently associated with the increased risk of ISR. In a mouse femoral artery wire injury model, upregulated OPG was evidenced in vascular tissue after injury. OPG deletion attenuated the vascular injury-induced neointimal hyperplasia and related gene expression in mice. OPG promoted neointimal hyperplasia and human aortic smooth muscle cell (hASMC) proliferation and migration through activation of yes-associated protein (YAP), a major downstream effector of the Hippo signaling pathway, whereas knockdown or inhibition of YAP in hASMCs blunted OPG-induced above effects. Moreover, we found that OPG, as a ligand for integrin αVβ3, mediated phosphorylation of focal adhesion kinase (FAK) and actin cytoskeleton reorganization, resulting in YAP dephosphorylation in hASMCs. OPG-dependent YAP and VSMC activation was prevented by treatment with αVβ3-blocking antibodies and inhibitors of FAK and actin stress fibers.. Increased serum OPG levels are associated with increased risk of ISR following PCI and OPG could promote neointimal hyperplasia in response to injury through integrin αVβ3 mediated FAK and YAP activation, indicating OPG/YAP inhibition might serve as an attractive novel target for the prevention of ISR after PCI.

Topics: Actin Cytoskeleton; Aged; Animals; Cell Movement; Cell Proliferation; Coronary Restenosis; Disease Progression; Female; Femoral Artery; Focal Adhesion Protein-Tyrosine Kinases; Humans; Hyperplasia; Incidence; Integrin alphaVbeta3; Logistic Models; Male; Mice, Inbred C57BL; Multivariate Analysis; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Osteoprotegerin; Phosphorylation; Severity of Illness Index; Signal Transduction; Stents; Up-Regulation; Verteporfin