This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 96/12/1248    most recent 01.RES.0000171451.88616.c2v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nadra, I. Articles by Haskard, D. O. Search for Related Content PubMed PubMed Citation Articles by Nadra, I. Articles by Haskard, D. O. Related Collections Other Vascular biology Pathophysiology Cell signalling/signal transduction Related Article

(Circulation Research. 2005;96:1248.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways

A Vicious Cycle of Inflammation and Arterial Calcification?

Imad Nadra, Justin C. Mason, Pandelis Philippidis, Oliver Florey, Cheryl D.W. Smythe, Geraldine M. McCarthy, Robert C. Landis, Dorian O. Haskard

From the British Heart Foundation Cardiovascular Medicine Unit (I.M., J.C.M., P.P., O.F., C.D.W.S., R.C.L., D.O.H.), Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London; and the Department of Clinical Pharmacology (G.M.M.), The Royal College of Surgeons, Dublin. The current address of R.C.L. is the Edmund Cohen Laboratory for Vascular Research, Chronic Disease Research Centre, Tropical Medicine Research Institute, UWI, Barbados, West Indies.

Correspondence to Dr D.O. Haskard, British Heart Foundation Cardiovascular Medicine Unit, Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Rd, London, W12 ONN UK. E-mail d.haskard{at}imperial.ac.uk

Basic calcium phosphate (BCP) crystal deposition underlies the development of arterial calcification. Inflammatory macrophages colocalize with BCP deposits in developing atherosclerotic lesions and in vitro can promote calcification through the release of TNF alpha. Here we have investigated whether BCP crystals can elicit a proinflammatory response from monocyte-macrophages. BCP microcrystals were internalized into vacuoles of human monocyte-derived macrophages in vitro. This was associated with secretion of proinflammatory cytokines (TNF, IL-1ß and IL-8) capable of activating cultured endothelial cells and promoting capture of flowing leukocytes under shear flow. Critical roles for PKC, ERK1/2, JNK, but not p38 intracellular signaling pathways were identified in the secretion of TNF alpha, with activation of ERK1/2 but not JNK being dependent on upstream activation of PKC. Using confocal microscopy and adenoviral transfection approaches, we determined a specific role for the PKC-alpha isozyme. The response of macrophages to BCP crystals suggests that pathological calcification is not merely a passive consequence of chronic inflammatory disease but may lead to a positive feed-back loop of calcification and inflammation driving disease progression.

Key Words: atherosclerosis pathophysiology • cell biology • calcification • inflammation • macrophage

Related Article:

Proinflammatory Vascular Calcification

Kristina Boström
Circ. Res. 2005 96: 1219-1220. [Full Text] [PDF]

This article has been cited by other articles:

				A. E. Ewence, M. Bootman, H. L. Roderick, J. N. Skepper, G. McCarthy, M. Epple, M. Neumann, C. M. Shanahan, and D. Proudfoot Calcium Phosphate Crystals Induce Cell Death in Human Vascular Smooth Muscle Cells: A Potential Mechanism in Atherosclerotic Plaque Destabilization Circ. Res., August 29, 2008; 103(5): e28 - e34. [Abstract] [Full Text] [PDF]

				E. S. Molloy, M. P. Morgan, G. A. Doherty, B. McDonnell, M. Hilliard, J. O'Byrne, D. J. Fitzgerald, and G. M. McCarthy Mechanism of basic calcium phosphate crystal-stimulated cyclo-oxygenase-1 up-regulation in osteoarthritic synovial fibroblasts Rheumatology, July 1, 2008; 47(7): 965 - 971. [Abstract] [Full Text] [PDF]

				L. L. Demer and Y. Tintut Vascular Calcification: Pathobiology of a Multifaceted Disease Circulation, June 3, 2008; 117(22): 2938 - 2948. [Full Text] [PDF]

				C. M. Shanahan Inflammation Ushers in Calcification: A Cycle of Damage and Protection? Circulation, December 11, 2007; 116(24): 2782 - 2785. [Full Text] [PDF]

				E. Aikawa, M. Nahrendorf, J.-L. Figueiredo, F. K. Swirski, T. Shtatland, R. H. Kohler, F. A. Jaffer, M. Aikawa, and R. Weissleder Osteogenesis Associates With Inflammation in Early-Stage Atherosclerosis Evaluated by Molecular Imaging In Vivo Circulation, December 11, 2007; 116(24): 2841 - 2850. [Abstract] [Full Text] [PDF]

				D. V. Anand, E. Lim, D. Darko, P. Bassett, D. Hopkins, D. Lipkin, R. Corder, and A. Lahiri Determinants of Progression of Coronary Artery Calcification in Type 2 Diabetes: Role of Glycemic Control and Inflammatory/Vascular Calcification Markers J. Am. Coll. Cardiol., December 4, 2007; 50(23): 2218 - 2225. [Abstract] [Full Text] [PDF]

				T. Y Tang, S. P S Howarth, S. R Miller, M. J Graves, J.-M. U-King-Im, R. A Trivedi, Z. Y. Li, S. R Walsh, A. P Brown, P. J Kirkpatrick, et al. Comparison of the inflammatory burden of truly asymptomatic carotid atheroma with atherosclerotic plaques contralateral to symptomatic carotid stenosis: an ultra small superparamagnetic iron oxide enhanced magnetic resonance study J. Neurol. Neurosurg. Psychiatry, December 1, 2007; 78(12): 1337 - 1343. [Abstract] [Full Text] [PDF]

				L. J. Schurgers, H. M. H. Spronk, B. A. M. Soute, P. M. Schiffers, J. G. R. DeMey, and C. Vermeer Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats Blood, April 1, 2007; 109(7): 2823 - 2831. [Abstract] [Full Text] [PDF]

				B. J. Bennett, M. Scatena, E. A. Kirk, M. Rattazzi, R. M. Varon, M. Averill, S. M. Schwartz, C. M. Giachelli, and M. E. Rosenfeld Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE-/- Mice Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 2117 - 2124. [Abstract] [Full Text] [PDF]

				J. R. Crouse III Thematic review series: Patient-Oriented Research. Imaging atherosclerosis: state of the art J. Lipid Res., August 1, 2006; 47(8): 1677 - 1699. [Abstract] [Full Text] [PDF]

				D. V. Anand, A. Lahiri, E. Lim, D. Hopkins, and R. Corder The Relationship Between Plasma Osteoprotegerin Levels and Coronary Artery Calcification in Uncomplicated Type 2 Diabetic Subjects J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1850 - 1857. [Abstract] [Full Text] [PDF]

				D. Yuen, A. Pierratos, R. M.A. Richardson, and C. T. Chan The natural history of coronary calcification progression in a cohort of nocturnal haemodialysis patients Nephrol. Dial. Transplant., May 1, 2006; 21(5): 1407 - 1412. [Abstract] [Full Text] [PDF]

				C. M. Shanahan Vascular calcification--a matter of damage limitation? Nephrol. Dial. Transplant., May 1, 2006; 21(5): 1166 - 1169. [Full Text] [PDF]

				H. M.H. Spronk Vitamin K Epoxide Reductase Complex and Vascular Calcification: Is This the Important Link Between Vitamin K and the Arterial Vessel Wall? Circulation, March 28, 2006; 113(12): 1550 - 1552. [Full Text] [PDF]

				K. Bostrom Proinflammatory Vascular Calcification Circ. Res., June 24, 2005; 96(12): 1219 - 1220. [Full Text] [PDF]