ERK-1/-2 and p38 Kinase Oppositely Regulate 15-deoxy-delta(12,14)-prostaglandinJ2-Induced PPAR-gamma Activation That Mediates Dedifferentiation But Not Cyclooxygenase-2 Expression in Articular Chondrocytes

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated transcription factor and plays an important role in growth, differentiation, and inflammation in different tissues. In this study, we investigated the effects of 15d-PGJ2, a high-affinity ligand of PPAR-gamma, on dedifferentiation and on inflammatory responses such as COX-2 expression and PGE2 production in rabbit articular chondrocytes with a focus on ERK-1/-2, p38 kinase, and PPAR-gamma activation. We report here that 15d-PGJ2 induced dedifferentiation and/or COX-2 expression and subsequent PGE2 production. 15d-PGJ2 treatment stimulated activation of ERK-1/-2, p38 kinase, and PPAR-gamma. Inhibition of ERK-1/-2 with PD98059 recovered 15d-PGJ2-induced dedifferentiation and enhanced PPAR-gamma activation, whereas inhibition of p38 kinase with SB203580 potentiated dedifferentiation and partially blocked PPAR-gamma activation. Inhibition of ERK-1/-2 and p38 kinase abolished 15d-PGJ2-induced COX-2 expression and subsequent PGE2 production. Our findings collectively suggest that ERK-1/-2 and p38 kinase oppositely regulate 15d-PGJ2-induced dedifferentiation through a PPAR-gamma-dependent mechanism, whereas COX-2 expression and PGE2 production is regulated by ERK-1/-2 through a PPAR-gamma-independent mechanism but not p38 kinase in articular chondrocytes. Additionally, these data suggest that targeted modulation of the PPAR-gamma and mitogen-activated protein kinase pathway may offer a novel approach for therapeutic inhibition of joint tissue degradation.

15-Deoxy-delta 12,14-ProstaglandinJ2 Regulates Dedifferentiation through Peroxisome Proliferator-Activated Receptor-gamma-Dependent Pathway but Not COX-2 Expression in Articular Chondrocytes

Peroxisome proliferator-activated receptors-gamma (PPAR-gamma) is critical for phenotype determination at early differentiation stages of mesenchymal cells, whereas its physiological role is unclear. Therefore, we investigated the role of 15-deoxy-delta 12,14-prostaglandinJ2 (15d-PGJ2), the natural receptor ligand for PPAR-gamma, on dedifferentiation and inflammatory responses, such as COX-2 expression and PGE2 production, in articular chondrocytes. Our data indicate that the 15d-PGJ2 caused a loss of differentiated chondrocyte phenotype as demonstrated by inhibition of type II collagen and proteoglycan synthesis. 15d-PGJ2 also induced COX-2 expression and PGE2 production. The 15d-PGJ2-induced dedifferentiation effect seems to be dependent on PPAR-gamma activation, as the PPRE luciferase activity increased and PPAR-gamma antagonist, BADGE, abolished type II collagen expression. However, BADGE did not block 15d-PGJ2-induced COX-2 expression. Collectively, our findings suggest that PPAR-gamma-dependent and -independent mechanisms of 15d-PGJ2-induced dedifferentiation and inflammatory responses in articular chondrocytes, respectively. Additionally, these data suggest that targeted modulation of the PPAR-gamma pathway may offer a novel approach for therapeutic inhibition of joint tissue degradation.

Src Kinase Regulates Nitric Oxide-induced Dedifferentiation and Cyclooxygenase-2 Expression in Articular Chondrocytes via p38 Kinase-dependent Pathway

BACKGROUND: Nitric oxide (NO) in articular chondrocytes regulates dedifferentiation and inflammatory responses by modulating MAP kinases. In this study, we investigated whether the Src kinase in chondrocytes regulates NO-induced dedifferentiation and cyclooxygenase-2 (COX-2) expression. METHODS: Primary chondrocytes were treated with various concentrations of SNP for 24 h. The COX-2 and type II collagen expression levels were determined by immunoblot analysis, and prostaglandin E(2) (PGE(2)) was determined by using a PGE(2) assay kit. Expression and distribution of p-Caveolin and COX-2 in rabbit articular chondrocytes and cartilage explants were determined by immunohistochemical staining and immunocytochemical staining, respectively. RESULTS: SNP treatment stimulated Src kinase activation in a dose-dependent manner in articular chondrocytes. The Src kinase inhibitors PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine], a significantly blocked SNP-induced p38 kinase and caveolin-1 activation in a dose-dependent manner. Therefore, to determine whether Src kinase activation is associated with dedifferentiation and/or COX-2 expression and PGE(2) production. As expected, PP2 potentiated SNP-stimulated dedifferentiation, but completely blocked both COX-2 expression and PGE2 production. And also, levels of p-Caveolin and COX-2 protein expression were increased in SNP-treated primary chondrocytes and osteoarthritic and rheumatoid arthritic cartilage, suggesting that p-Caveolin may play a role in the inflammatory responses of arthritic cartilage. CONCLUSION: Our previously studies indicated that NO caused dedifferentiation and COX-2 expression is regulated by p38 kinase through caveolin-1 (1). Therefore, our results collectively suggest that Src kinase regulates NO-induced dedifferentiation and COX-2 expression in chondrocytes via p38 kinase in association with caveolin-1.

Papillary Tumors of the Breast: US Findings of the Benign and Malignant Lesions

PURPOSE: To determine which sonographic findings usefully differentiate between benign and malignant papillary tumors. MATERIALS AND METHODS: We retrospectively rev i ewed the ultrasonographic findings of 42 surgically proven cases of papillary breast lesions [11 malignant lesions (7 inva s i ve papillary carcinomas, 4 intraductal papillary carcinomas) and 31 benign intraductal pa-pillomas]. All 42 cases were classified sonographically as cystic or ductal, or solid type, and the shape, wall change, margin, internal echo-pattern, posterior echo change and other associated findings for the two types were then analysed. RESULTS: Among the 25 cases (5 malignant and 20 benign) of cystic or ductal type, tubular shaped lesions were more frequently benign (60%). In all 20 benign lesions the wall of cystic portion was well-defined, smooth and thin. The solid portion of the cystic type showed an illdefined irregular margin in four malignant lesions (80%) and a smooth margin in 19 which were benign (95%). The internal echo-pattern was heterogeneous mixed-echo in three cases of malignancy, and homogeneously hypoechoic in 19 benign lesions (95%). Posterior enhancement was seen in two malignant lesions (40%), while in 19 benign lesions (95%), there was no posterior echo change. There were 17 solid type lesions (6 malignant cases, 11 benign cases), and most of these, whether benign or malignant, were smooth, oval or lobulated, hypoechoic masses. Posterior enhancement, howeve r, was more frequently observed in malignant lesions (three cases, 50%) than in those which were benign (one case, 9%). CONCLUSION: In cystic or ductal type lesions, an ill-defined irregular thick cystic wall, an illdefined irregular margin, a heterogeneous mixed internal echo-pattern and posterior enhancement of the solid portion suggested malignancy. In solid type lesions, posterior enhancement was more frequently found in malignant than in benign lesions.

Radiological analysis of normal mammogram

Two hundreds fifty seven cases of normal mammogram were analysis for classification of types of breasts.Ranging from 20 to 79 years of age, mean age was 45 years. Two projections, craniocaudal & mediolateral, were used. Age, nutrient condition, familial tendency and hormonal factors influence to breats hisologically. Normalbreats were classified into the standard (9.75%), ductal (71.7%), glandular (6.2%) and atrophic (12.4%) types.Ductal type was further subclassified into intraductal, periductal and mixed types. Atrophic type was susbdividedinto fibrous and fatty, Standard type was observed in younger women, instead of atrophic type was seen in olderage group, especially after menopause. Periductal type was most common (65.4%), Glandular type was mostly intwenty to thirty year group. According to increase of age, gladular or ductal type transformed into atrophic type.