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Superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance (MR) imaging has been used for the detection of hepatic tumors. However, little is known about this technique in relation to hepatocellular carcinoma (HCC).The aim of this study was to investigate whether SPIOenhanced MR imaging can be useful in assessing histological grades of HCC. The authors studied histologically proven tumors including 31 HCCs and 6 dysplastic nodules. The ratio of the Kupffer-cell count in the tumorous tissue relative to that in the nontumorous tissue (Kupffer-cell-count ratio) decreased as HCCs became less well differentiated. The ratio of the intensity of the tumorous lesion to that of the nontumorous area on SPIO-enhanced MR images (SPIO intensity ratio) correlated inversely with Kupffer-cell-count ratio in HCCs and dysplastic nodules (r ‫؍‬ ؊.826, P < .001) and increased as the degree of differentiation of HCCs decreased, indicating that the uptake of SPIO in HCCs decreased as the degree of differentiation of HCCs declined. All of the dysplastic nodules and some well-differentiated HCCs showed hypointense or isointense enhancement, relative to the surrounding liver parenchyma, indicating greater or similar uptake of SPIO in the tumor when compared with nontumorous areas. These results suggest that SPIO-enhanced MR imaging reflects Kupffer-cell numbers in HCCs and dysplastic nodules, and is useful for estimation of histological grading in HCCs, although uncertainties persist in differentiating dysplastic nodules from well-differentiated HCCs. (HEPATOLOGY 2000;32:205-212.) Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and a major cause of death in patients with cirrhosis. [1][2][3][4] One of the characteristics of HCC detected by imaging modalities such as computed tomography (CT), magnetic resonance (MR) imaging, and CT angiography, is increased arterial blood flow accompanied by decreased portal blood flow, although some well-differentiated HCCs do not show such blood supply characteristics. [5][6][7][8][9] Another characteristic of HCC, distinct from other metastatic tumors, has recently been clarified by Tanaka et al., 10 namely, that some well-differentiated HCCs have similar numbers of Kupffer cells as do the surrounding nontumorous regions of the liver.Superparamagnetic iron oxide (SPIO) is a tissue-specific MR imaging contrast that is taken up by Kupffer cells in the liver and macrophages in the spleen. 11,12 Because metastatic liver cancers lack Kupffer cells, hepatic metastases do not take up SPIO and thus appear hyperintense relative to the surrounding liver, being useful for the detection of metastatic liver cancers. [11][12][13][14] In an animal model of HCC, Kawamori et al., 15 studied whether SPIO-enhanced MR imaging could allow HCC to be distinguished from hyperplastic nodules. They concluded that SPIO-enhanced MR imaging may be useful in differentiating HCC from hyperplastic nodules, although some HCC nodules were difficult to differentiate from hyperplastic nodules, even after S...

In women, estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to osteoporosis, the most common skeletal disorder. However, mechanisms underlying osteoporosis resulting from estrogen deficiency remain largely unknown. Here we show that in bone-resorbing osteoclasts, estrogendependent destabilization of hypoxia-inducible factor 1 alpha (HIF1α), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1α was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1α in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1α inactivation antagonized bone loss in Ovx mice and osteoclast-specific estrogen receptor alpha deficient mice, both models of estrogen-deficient osteoporosis. Oral administration of a HIF1α inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1α represents a promising therapeutic target in osteoporosis.B one mass is tightly regulated by a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Estrogen loss in women after menopause frequently promotes activation of osteoclastic bone resorption, causing osteoporosis. Osteoporotic bone phenotypes are seen in ovariectomized female mice, and estrogen deficiency-induced bone loss in both mouse models and women is ameliorated by estrogen treatment (1, 2). However, estrogen administration reportedly increases risk of cardiovascular events and carcinogenesis of the mammary gland and uterus (3). Bioavailable estrogens including selective estrogen receptor modulators (SERMs) also protect bone from estrogen deficiency-induced osteoporosis (4), and estrogen and SERMs primarily act via estrogen receptors (ER), ERα and ERβ (5, 6). However, how SERMs act on bone remains largely unknown. Thus, understanding of osteoclast activation following estrogen loss is crucial for development of safe therapeutic reagents.Both the endosteal zone of bone marrow cavities and epiphyseal growth plates are hypoxic areas, and the hypoxia-inducible factor (HIF) signaling pathway governs chondrocyte and osteoblast function in these respective areas (7,8). The HIF1 transcription factor consists of an oxygen-regulated alpha subunit, HIF1α, and a constitutively expressed beta subunit, HIF1β. Under normoxia, HIF1α is posttranslationally modified by prolyl hydroxylases, which catalyze hydroxylation of proline residues in the presence of O 2 and Fe 2+ . Recognition of hydroxylated HIF1α by the von Hippel-Lindau tumor suppressor protein recruits an E3 ubiquitin ligase complex targeting HIF1α for proteasomal degradation. Conversely, under hypoxia, proline hydroxylation is inhibited by substrate (O 2 ) deprivation, allowing HIF1α accumulation and formation of an active transcriptional complex with HIF1β (9). Recently, regulation of HIF1α protein levels by factors other than O 2 , including reactive ...

Cell-cell fusion is a dynamic phenomenon promoting cytoskeletal reorganization and phenotypic changes. To characterize factors essential for fusion of macrophage lineage cells, we identified the multitransmembrane protein, osteoclast stimulatory transmembrane protein (OC-STAMP), and analyzed its function. OC-STAMP-deficient mice exhibited a complete lack of cell-cell fusion of osteoclasts and foreign body giant cells (FBGCs), both of which are macrophage-lineage multinuclear cells, although expression of dendritic cell specific transmembrane protein (DC-STAMP), which is also essential for osteoclast/FBGC fusion, was normal. Crossing OC-STAMP-overexpressing transgenic mice with OC-STAMP-deficient mice restored inhibited osteoclast and FBGC cell-cell fusion seen in OC-STAMP-deficient mice. Thus, fusogenic mechanisms in macrophage-lineage cells are regulated via OC-STAMP and DC-STAMP. ß