5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway.

      Circulation Research
      Animals, Aortic Diseases, chemically induced, metabolism, pathology, Bone Morphogenetic Protein 4, Calcinosis, Calcitriol, Carrier Proteins, Cells, Cultured, Disease Models, Animal, I-kappa B Kinase, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Nephrectomy, Osteoprotegerin, RANK Ligand, genetics, RNA Interference, RNA, Small Interfering, Rats, Rats, Sprague-Dawley, Receptor Activator of Nuclear Factor-kappa B, Signal Transduction

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Vascular calcification commonly associated with several pathologies and it has been suggested to be similar to bone mineralization. The axis RANKL-OPG (receptor activator of nuclear factor kappaB ligand-osteoprotegerin) finely controls bone turnover. RANKL has been suggested to increase vascular calcification, but direct evidence is missing. Thus, in the present work, we assess the effect of RANKL in vascular smooth muscle cell (VSMC) calcification. VSMCs incubated with RANKL showed a dose-dependent increase in calcification, which was abolished by coincubation with OPG. To test whether the effect was mediated by signaling to its receptor, knockdown of RANK was accomplished by short hairpin (sh)RNA. Indeed, cells lacking RANK showed no increases in vascular calcification when incubated with RANKL. To further elucidate the mechanism by which RANK activation increases calcification, we blocked both nuclear factor (NF)-kappaB activation pathways. Only IKKalpha inactivation inhibited calcification, pointing to an involvement of the alternative NF-kappaB activation pathway. Furthermore, RANKL addition increased bone morphogenetic protein (BMP)4 expression in VSMCs, and that increase disappeared in cells lacking RANK or IKKalpha. The increase in calcification was also blunted by Noggin, pointing to a mediation of BMP4 in the calcification induced by RANKL. Furthermore, in an in vivo model, the increase in vascular calcium content was parallel to an increase in RANKL and BMP4 expression, which was localized in calcified areas. However, blood levels of the ratio RANKL/OPG did not change. We conclude that RANKL increases vascular smooth muscle cell calcification by binding to RANK and increasing BMP4 production through activation of the alternative NF-kappaB pathway.

          Related collections

          Author and article information

          Comments

          Comment on this article