In vivo micro computed tomography of subchondral bone in the rat after intra-articular administration of monosodium iodoacetate.

Osteoarthritis (OA) is a degenerative disease that is characterized by joint discomfort, loss of articular cartilage, and changes to the subchondral bone. Studies to elucidate the pathophysiology of OA have been hampered by the lack of a rapid, reproducible animal model that mimics the structural changes associated with the disease. A single intra-articular injection of mono-iodoacetate (MIA), an inhibitor of glycolysis, into the femorotibial joint of rodents promotes loss of articular cartilage similar to that noted in human OA. The purpose of the present study was to determine whether in vivo three-dimensional micro computed tomography (microCT) was of use for detecting progressive changes over time to the subchondral bone (femorotibial joint) of Wistar rats treated with a single intra-articular injection of MIA. MIA-treated right knee joints and left contralateral control knee joints were imaged in vivo at 0, 1, 7, 14, 28, and 56 days postinjection by using microCT. Analysis of 50- and 100- micro m resolution images demonstrated that changes to the subchondral bone, as determined by visual and bone mineral density analysis, are apparent by day 14 post-MIA. By day 28, there were marked changes to lateral aspect of the medial tibial plateaus of the subchondral bone in MIA-treated joints. These changes were progressive through day 56. It was concluded that intra-articular injection of MIA induces progressive changes to subchondral bone that can be assessed using in vivo microCT imaging. In light of these data, in vivo microCT imaging represents a valuable tool for investigating bone remolding and has the potential to be used for routine, high-throughput analysis and screening of investigation therapeutics.

Pleiotropic effects of HMG-CoA reductase inhibitors.

HMG-CoA reductase, in addition to being the rate-limiting enzyme in the cholesterol biosynthetic pathway, is involved in the regulation of receptors for low-density lipoprotein (LDL)-cholesterol. Clinical studies in men and women demonstrate that inhibitors of HMG-CoA reductase (statins), by reducing plasma cholesterol, may limit the development of atherosclerosis and reduce the risk of mortality and ischemic events. Preclinical evidence suggests that under controlled conditions of plasma cholesterol lowering, statins may have ancillary properties or pleiotropic effects, which may directly limit atherosclerosis progression. In this review, pleiotropic effects have been defined as 'ancillary properties of statins, which result in hepatic and/or vascular changes that may or may not be a consequence of inhibition of HMG-CoA reductase.' Beyond the LDL lowering activity of statins, improvements have been noted in endothelial dysfunction through direct stimulation of expression of such vasodilators as nitric oxide and/or reduction in vasoconstrictors. Factors associated with atherogenesis, such as monocyte adhesion to endothelial cells, macrophage production of proinflammatory molecules and matrix metalloproteases, smooth muscle cell proliferation and migration and macrophage-induced oxidation of LDL particles have also been reduced by various statins. It is unclear whether the observed pleiotropic effects are independent of LDL-cholesterol lowering or inhibition of HMG-CoA reductase, and whether they are clinically relevant; however, one can conclude that the pleiotropic effects appear to be a class effect of statins and can be attenuated by addition of the post-reductase product, mevalonate.

Extracellular matrix metalloproteinase inducer (EMMPRIN) is induced upon monocyte differentiation and is expressed in human atheroma.

OBJECTIVE: Because extracellular matrix metalloproteinase inducer (EMMPRIN), a tumor cell-derived protein, induces matrix metalloproteinases (MMPs) in fibroblasts and because MMPs are important in atheroma formation, we investigated if EMMPRIN was expressed in granulocyte/macrophage-colony stimulating factor (GM-CSF)-differentiated human peripheral blood monocytes (HPBM) and macrophage foam cells. In addition, EMMPRIN was studied for its expression in human atheroma. METHODS AND RESULTS: After 10 days of GM-CSF-induced monocyte differentiation, EMMPRIN mRNA increased 5- to 8-fold relative to undifferentiated monocytes. GM-CSF treatment of HPBM revealed that both EMMPRIN mRNA and protein were upregulated by day 2 over undifferentiated monocytes. GM-CSF-differentiated HPBM showed characteristic macrophage phenotype by showing increases in pancake-like morphology and increases in biochemical markers such as apolipoprotein E, MMP-9, and cholesterol ester (CE). While acetylated LDL treatment of the 10-day GM-CSF-differentiated HPBM increased CE mass 13- to 321-fold, EMMPRIN expression was unchanged relative to nonlipid-loaded macrophages. In human coronary atherosclerotic samples, EMMPRIN was observed in CD68(+) macrophage-rich areas as well as areas of MMP-9 expressions. CONCLUSIONS: Based on these data, we conclude that monocyte differentiation induces EMMPRIN expression, CE enrichment of foam cells has no further effect on EMMPRIN expression, and EMMPRIN is present in human atheroma. Therefore, EMMPRIN may play a role in atherosclerosis development.