EDITORIAL

Macrophage Glucocorticoid Receptors Join the Intercellular Dialogue in Atherosclerotic Lesion Calcification .

Robert Terkeltaub, M.D. .

Department of Medicine, Rheumatology Section, VA Health Care System/UCSD, San Diego, CA, 92161 Correspondence to: Robert Terkeltaub, MD, VA Medical Center, Rheumatology, 3350 La Jolla Village Drive, San Diego, CA 92161. Telephone 858-552-8585, ext 3519. Fax 858-552-7425. E-mail: rterkeltaub@ucsd.edu .

Arterial calcification is one of the potential phenotypes of vascular remodeling and repair in atherosclerosis, diabetes, hyperphosphatemic renal failure, and aging (1-3). Calcification decreases arterial wall compliance (4). Furthermore, deposited crystalline apatite can activate macrophages, resulting in a proinflammatory phenotype. Consequently, arterial calcification localized to the intima is a potential biomarker of atherosclerosis, and is linked to disease progression and cardiovascular mortality, while arterial calcification localized primarily to the tunica media promotes mortality in diabetes and renal failure (4). In addition, calcific stenosis of the aortic valve is a prevalent and highly significant public health problem, and shares such pathophysiological features as ectopic chondro-osseous differentiation in common with arterial calcification (5).In a study published in the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Preusch et al report the effects of lineage-specific deletion of the glucocorticoid receptor (GR) in bone marrow-donor macrophages on chondro-osseous differentiation and calcification in dietary - induced atherosclerotic lesions in lethally irradiated, bone marrow transplant recipient, LDLR knockout mice (6). Arterial calcification appears to be an active and organized multicellular process, which is switched on by chondro-osseous differentiation of a variety of progenitors in the artery wall, and regulated in part by systemic influences. Such influences include the effects of calciotropic hormones and of mineral nucleation promoters and inhibitors (1-4). In the intralesional intercellular dialogue that drives vascular calcification, potential progenitors of calcifying osteoblastic and chondrocytic cells include not only pericytes and resident and recruited vascular stem cells, but also non-terminally differentiated, phenotypically plastic adventitial myofibroblasts and smooth muscle cells (SMCs). Significantly, the latter may undergo chondro-osseous trans-differentiation (1-5,7-12).Intralesional mechanisms that drive chondro-osseous differentiation in arterial calcification include an excess of inducers of chondro-osseous commitment and maturation, such as BMP2, Pi generation and uptake by SMCs, and signaling stimulated by the wnt beta-catenin axis and by transglutaminase 2 (1-5,7-12). Conversely, intralesional deficiency of physiologic inhibitors of chondro-osseous differentiation also plays a role in arterial calcification, as exemplified by the linkage of spontaneous intra-arterial chondrogenesis and calcification with paucity of the BMP2 inhibitor and matrix calcification inhibitor MGP (13), or of the chondrogenic and matrix calcification inhibitor PPi (9,14). .

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