Invited commentary

Abstract

Precision medicine and molecular therapeutics offer significant potential in vascular patients because of the chronicity and heterogeneity of disease. Currently, there is no established, targeted molecular therapeutic intervention for abdominal aortic aneurysm (AAA) disease. The work on using metalloproteinase as a biomarker and targeting its activity as a therapeutic option continues on the basis of earlier work, in whole and in part, in murine models. Initial studies in humans have not come to fruition.1Golledge J. Norman P.E. Murphy M.P. Dalman R.L. Challenges and opportunities in limiting abdominal aortic aneurysm growth.J Vasc Surg. 2017; 65: 225-233Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Other potential biologic interventions have also proved unsuccessful. Thus, a greater understanding of AAA pathobiology and the identification of one or more ligand or intracellular pathways that can interrupt the pathobiologic process of aneurysm formation remain important areas of study. The current study sheds more light on receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclastogenic differentiation of macrophages in a phenotypically unique model of AAA formation. Several studies have demonstrated that there is a balanced mineralization process within the wall of diseased arteries mediated by monocyte-macrophage-derived osteoblast-like and osteoclast-like cells.2Yamanouchi D. Takei Y. Komori K. Balanced mineralization in the arterial system: possible role of osteoclasto-genesis/osteoblasto-genesis in abdominal aortic aneurysm and stenotic disease.Circ J. 2012; 76: 2732-2737Crossref PubMed Scopus (27) Google Scholar Osteoclastogenic activation of macrophages has been described both in human AAAs and in experimental aneurysm formation. Mature osteoclasts express matrix metalloproteinase 9, which provides an iterative link back to the original hypotheses that matrix metalloproteinases have a role in AAA formation. The current study builds on this background and shows that osteoclast-like macrophages in AAA are associated with increased expression of RANKL.2Yamanouchi D. Takei Y. Komori K. Balanced mineralization in the arterial system: possible role of osteoclasto-genesis/osteoblasto-genesis in abdominal aortic aneurysm and stenotic disease.Circ J. 2012; 76: 2732-2737Crossref PubMed Scopus (27) Google Scholar Administration of a RANKL-neutralizing antibody resulted in a significant decrease in the diameter of the experimental aneurysms. This would suggest that targeting RANKL may be a potential new therapeutic approach to inhibition of AAA growth. RANKL neutralization is currently used clinically to treat osteoporosis and other osteoclast-related diseases; thus, a medication and therapeutic profile in humans already exists. The importance of this paper is that it identifies a unique target within macrophages that reside within the wall of an AAA and this target has a known therapeutic antagonist in clinical practice. However, given the uniqueness of the model with a phenotype of a dissecting aortic aneurysm, validation in the other murine and nonmurine models of AAA will be necessary. Once validated, there will be a need to define the timing for RANKL intervention, to ensure precision in homing and targeting to an aneurysmal aortic wall, to estimate the duration of therapy (acute, pulsed, or chronic), and to ensure that there are no unintended cellular consequences in other arteries and organs. Irrespective of these issues, the current study reveals a novel and new pathway to interrupt AAA formation that has prospects to move to a clinical study and marks an advance in the understanding of the role of macrophages in AAA pathobiology. The opinions or views expressed in this commentary are those of the authors and do not necessarily reflect the opinions or recommendations of the Journal of Vascular Surgery or the Society for Vascular Surgery. RANKL-mediated osteoclastogenic differentiation of macrophages in the abdominal aorta of angiotensin II-infused apolipoprotein E knockout miceJournal of Vascular SurgeryVol. 68Issue 6PreviewOsteoclastogenic activation of macrophages (OCG) occurs in human abdominal aortic aneurysms (AAAs) and in calcium chloride-induced degenerative AAAs in mice, which have increased matrix metalloproteinase activity. As the activity of OCG in dissecting aneurysms is not clear, we tested the hypothesis that OCG contributes to angiotensin II (Ang II)-induced dissecting aneurysm (Ang II-induced AAA) in apolipoprotein E knockout mice. Full-Text PDF Open Archive