Physiological exercise loading suppresses post-traumatic osteoarthritis progression via an increase in bone morphogenetic proteins expression in an experimental rat knee model.

OBJECTIVE: To evaluate the dose-response relationship of exercise loading in the cartilage-subchondral bone (SB) unit in surgically-induced post-traumatic osteoarthritis (PTOA) of the knee. DESIGN: Destabilized medial meniscus (DMM) surgery was performed on the right knee of 12-week-old male Wistar rats, and sham surgery was performed on the contralateral knee. Four weeks after the surgery, the animals were subjected to moderate (12 m/min) or intense (21 m/min) treadmill exercises for 30 min/day, 5 days/week for 4 weeks. PTOA development in articular cartilage and SB was examined using histological and immunohistochemical analyses, micro-computed tomography (micro-CT) analysis, and biomechanical testing at 8 weeks after surgery. Gremlin-1 was injected to determine the role of bone morphogenetic protein (BMP) signaling on PTOA development following moderate exercise. RESULTS: Moderate exercise increased BMP-2, BMP-4, BMP-6, BMP receptor 2, pSmad-5, and inhibitor of DNA binding protein-1 expression in the superficial zone chondrocytes and suppressed cartilage degeneration, osteophyte growth, SB damage, and osteoclast-mediated SB resorption. However, intense exercise had little effect on BMP expression and even caused progression of these osteoarthritis (OA) changes. Gremlin-1 injection following moderate exercise caused progression of the PTOA development down to the level of the non-exercise DMM-operated knee. CONCLUSIONS: Exercise regulated cartilage-SB PTOA development in DMM-operated knees in a dose-dependent manner. Our findings shed light on the important role of BMP expression in superficial zone chondrocytes in attenuation of PTOA development following physiological exercise loading. Further studies to support a mechanism by which BMPs would be beneficial in preventing PTOA progression are warranted.

p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation.

The stress-responsive p38 MAPK, when activated by genotoxic stresses such as UV radiation, enhances p53 activity by phosphorylation and leads to cell cycle arrest or apoptosis. Here we report that a member of the protein phosphatase type 2C family, Wip1, has a role in down-regulating p38-p53 signaling during the recovery phase of the damaged cells. Wip1 was originally identified as a gene whose expression is induced following gamma or UV radiation in a p53-dependent manner. We found that Wip1 is also inducible by other environmental stresses, such as anisomycin, H(2)O(2) and methyl methane sulfonate. UV-induction of Wip1 requires p38 activity in addition to the wild-type p53. Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue. Furthermore, Wip1 expression attenuates UV-induced p53 phosphorylation at Ser33 and Ser46, residues previously reported to be phosphorylated by p38. Wip1 expression also suppresses both p53-mediated transcription and apoptosis in response to UV radiation. These results suggest that p53-dependent expression of Wip1 mediates a negative feedback regulation of p38-p53 signaling and contributes to suppression of the UV-induced apoptosis.

Frequent allelic imbalance on chromosome 18q21 in early superficial colorectal cancers.

Genetic alterations in early superficial colorectal cancers have rarely been reported. In the present study, we searched for alterations in the APC and p53 genes in 27 superficial (20 depressed and 7 elevated) and 21 protruding colorectal cancers with submucosal invasion by means of PCR-single strand conformation polymorphism. Allelic imbalance (AI) on five loci, i.e., 1p34-36, 8p21-22, 14q32, 18q21 and 22q12-13, was also analyzed. Since a high incidence of 18q21 AI was detected in the superficial depressed cases, we further screened for alterations in Smad2, Smad4 and DCC. APC alterations were observed in three superficial depressed, one superficial elevated, and 11 protruding colorectal cancers, indicating that the frequency of APC alterations in superficial depressed cases was significantly lower than that in the protruding ones. There was no significant association between p53 alterations and macroscopic types. AI on 18q21 (13/20, 65%) was much higher than those on the other four loci in the superficial depressed cases. Moreover, the frequency of 18q21 AI in the superficial depressed cases was significantly higher than that in the protruding ones. Smad4 alterations were only detected in 1 of the 13 superficial depressed and 3 of the 17 protruding cases, while Smad2 and DCC alterations were not detected in any case examined. These data suggest that the carcinogenetic pathways of protruding and superficial depressed colorectal cancers are different, and that alterations of tumor suppressor gene(s) located on 18q21 other than Smad2, Smad4 and DCC might be associated with most superficial depressed colorectal cancers.

Cyclin D1 gene amplification in esophageal carcinosarcoma shown by differential polymerase chain reaction.

We studied cyclin D1 gene amplification in four esophageal carcinosarcomas using the differential polymerase chain reaction. Three cases showed amplification in the sarcomatous components, and one of these also showed amplification in the carcinomatous component. No amplification was detected in the other case. We also examined p53 expression in these four tumors by immunostaining. Both components of all four cases showed diffuse overexpression of p53 protein in the nuclei. Our results showed that the cyclin D1 gene is frequently amplified in esophageal carcinosarcoma, especially in the sarcomatous component. Two cases showed amplification only in the sarcomatous component, suggesting that amplification may have a role in the pathogenesis of that component of this malignancy. The diffuse overexpression of p53 observed in both components suggests that such overexpression, which could be the result of somatic mutation, might be an early event in the pathogenesis of esophageal carcinosarcoma.

The effect of ultraviolet rays on the prevention of exit-site infections.

The aim of this study was to show that ultraviolet (UV) irradiation to the skin around the catheter exit site (ES) could inhibit its infection. First, bacterial cultures of swabbed fluid from the ES were obtained from 68 continuous ambulatory peritoneal dialysis (CAPD) outpatients six times during the 24-month observation period. Second, the bactericidal effects of UV irradiation on the catheter ES were examined. The results were as follows: (1) In spite of disinfection of the catheter ES by the strict application of povidone-iodine once or twice a day, 23%-45% of the cases were found to be micro-organism positive. The most prevalent micro-organisms from the catheter ES were, in order of highest to lowest prevalence, Staphylococcus epidermidis (SE), Staphylococcus aureus (SA), and Pseudomonas aeruginosa (PA). (2) In the nasal cavity SA was detected in 20%-25% of patients. There was a high incidence of ES infection among the SA nasal carriers. (3) UV irradiation was performed in 18 cases that constantly revealed bacteria on culture at the catheter ES. Ten cases (55%) became culture-negative, 3 cases showed a microbial decrease, and 5 cases remained unchanged. These results suggest that UV irradiation can eliminate bacteria and can be of prophylactic use for ES infections.

Coexpression of intermediate-sized filaments in sialadenoma papilliferum and other salivary gland neoplasms.

The neoplastic cells present in a sialadenoma pappiliferum were found by immunoperoxidase method and immunofluorescent staining technique to co-express 3 different types of intermediate-sized filaments (IFs) defined by monoclonal antibodies to cytokeratin, vimentin and desmin. When other salivary gland tumors such as 18 pleomorphic adenomas, 15 adenolymphomas, 2 oxyphilic adenomas, 7 mucoepidermoid tumors, 5 acinic cell tumors, 8 adenoid cystic carcinomas and 6 adenocarcinomas were examined immunohistochemically for the expression of IFs, no tumors with all 3 types of IFs observed in sialadenoma papilliferum were found.

Immunopathological study of neuropeptide expression in human salivary gland neoplasms.

The immunoreactivity of anti-neuron-specific enolase (NSE) and anti-Leu-7 on formalin-fixed sections of human salivary gland neoplasms was determined by the avidin-biotin-peroxidase complex method. In addition, neuropeptides, such as vasoactive intestinal polypeptide, somatostatin, and substance P, in human salivary gland neoplasms were expressed, whereas other polypeptides, including glucagon, cholecystokinin, leu-enkephalin and calcitonin, were absent. When 182 paraffin-embedded examples of human salivary gland tumors, including 112 benign and 70 malignant neoplasms, were examined immunohistochemically, positive immunoreactivity was observed in: 51 cases with NSE (59%) and 46 cases with Leu-7 (54%) of 86 pleomorphic adenomas; 11 cases with Leu-7 (61%) of 18 Warthin's tumors; 7 cases with Leu-7 (58%) of 12 acinic cell carcinomas; 5 cases with NSE (31%) of 16 adenoid cystic carcinomas; 5 cases with NSE (42%) and 4 cases with Leu-7 (33%) of 12 adenocarcinomas; 4 cases with NSE (25%) and 6 cases with Leu-7 (38%) of 16 undifferentiated carcinomas. The other tumors, such as oxyphilic adenomas, basal cell adenomas, epidermoid carcinomas, and mucoepidermoid carcinomas, were nonreactive. Neuropeptides were observed in the neoplastic epithelial cells of certain tumors such as Warthin's tumors, acinic cell carcinomas, adenocarcinomas and undifferentiated carcinomas. These findings suggest the possibility that cells of neuroendocrine origin, present in certain neoplastic salivary gland epithelia may play a significant role in the histogenesis of human salivary gland neoplasms.