title: Vascular calcification in type-2 diabetes and cardiovascular disease: Integrative roles for OPG, RANKL and TRAIL.
abstract: Vascular calcification (VC), a disorder that causes blood vessel hardening and dysfunction, is a significant risk factor for type-2 diabetes mellitus (T2DM), which invariably manifests associated cardiovascular complications. Although the clinical effects of VC have been well-documented, the precise cellular events underlying the manifestation and progression of VC are only now coming to light. Current research models indicate that VC likely involves signalling pathways traditionally associated with bone remodelling, such as the OPG/RANKL/TRAIL signalling system. In this respect, receptor activator of NF-κB ligand (RANKL) promotes VC whilst osteoprotegerin (OPG) acts as a RANKL decoy receptor to block this effect, events that contrast with the known functional influence of these proteins during bone metabolism. Moreover, evidence suggests that tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), an alternative decoy ligand for OPG, may exert an anti-calcific influence within the vasculature. In the current review, we conduct a timely examination of this complex VC pathology from both mechanistic and therapeutic perspectives. Our objectives are twofold: (i) to critically assess our current understanding of both osteogenic and vascular calcification pathways, with particular focus on the co-interactive roles of OPG, RANKL, and TRAIL. Extensive in vitro, in vivo, and clinical studies will therefore be reviewed and critical findings highlighted; and (ii) to examine a range of therapeutic approaches of potential relevance to VC pathology. In this regard, a clear focus on VC as it applies to T2DM and cardiovascular disease (and particularly atherosclerosis) will be maintained.
authors.affiliation: School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland. Electronic address: emma.harper2@mail.dcu.ie.
authors.forename: Emma
authors.initials: E
authors.lastname: Harper
authors.affiliation: School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland; Department of Academic Endocrinology, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Hannah
authors.initials: H
authors.lastname: Forde
authors.affiliation: Department of Academic Endocrinology, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Colin
authors.initials: C
authors.lastname: Davenport
authors.affiliation: Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Rochfort
authors.affiliation: Department of Academic Endocrinology, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Diarmuid
authors.initials: D
authors.lastname: Smith
authors.affiliation: School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Cummins
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002317:Cardiovascular Agents / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000378:metabolism* / Q000627:therapeutic use; D058226:Plaque, Atherosclerotic; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000627:therapeutic use; D061205:Vascular Calcification / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
chemical_list: D002317:Cardiovascular Agents; D053244:Osteoprotegerin; D053245:RANK Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C506030:TNFRSF11B protein, human; C505653:TNFSF10 protein, human; C505688:TNFSF11 protein, human
keywords: OPG; RANKL; TRAIL; Type-2 diabetes mellitus; Vascular calcification