ABSTRACT. Degenerative lesions were induced in the knee joint of Wistar rats by intraarticular injection of chondrocyte metabolism inhibitor mono-iodoacetate (MIA) at doses of 0, 0.3 or 3 mg/joint. Histopathological examination and the measurement of hind paw weight ratio as an index of joint pain by incapacitance tester were performed. Histological findings that are similar to those observe d in human osteoarthritis (OA), such as disorganization of chondrocytes, erosion and fibrillation of cartilage surface, and subchondral bon e exposure etc., were observed in a MIA-dose-dependent manner. Saflanin-O fast green staining revealed that marked diffuse reduction of proteoglycan in cartilage tissue of rats treated with MIA. The clinical scores of the joint pain were closely correlated to the grade of histological findings. We conclude that the present experimental model in combination with a novel dual channel weight averager would be very useful for the study of human OA, and could be applied for estimation of therapeutic effect of new anti-OA drugs. KEY WORDS: mono-iodoacetate, osteoarthritis, pain assessment, rat.J. Vet. Med. Sci. 65(11): 1195-1199, 2003 Osteoarthritis (OA) is a degenerative joint disease characterized by fibrillation and erosion in cartilage tissue, chondrocyte proliferation and osteophyte formation at the joint margins, and sclerosis of subchondral bone [13]. Reportedly, imbalance occurs between synthetic and degenerative process within chondrocytes that leads to the net loss of cartilage tissue and subsequent pathologic condition [2]. At late stage of human OA, articular damages eventually lead to clinical findings such as joint impairment and pain.Although human OA-like lesions may occur spontaneously in dogs and mice, they are not appropriate for the evaluation of new anti-OA therapeutic agents because of low incidence and variable onset [5,16]. There are number of animal OA models that has variety of etiologies such as surgical induction [11, 12, 15], collagenase-induced [9], extracellular matrix loss [18,19], or impact-induced trauma [10]. However, studies on a new therapeutic drug for human OA and associated pain have been hampered because of the lack of useful animal model that closely mimic the human OA. Some study groups have previously reported that chondrocyte metabolism inhibitor mono-iodoacetate (MIA) have been reported to induce the disruption of glycolysis and subsequent cell death, and the loss of chondrocytes results in histologic changes in the knee joint resembling to human OA [6,17]. The objective of the present study is to clarify the histopathologic changes in MIA-induced knee joint lesion in the rats and its correlation to the dose of MIA and clinical pain evaluated by dual channel weight averager, with a development trial of non-invasive rat OA model for new drug development. MATERIALS AND METHODS Animals:Seven weeks old female Wistar rats were purchased from Charles River Japan Inc. (Yokohama, Kanagawa) and kept in air-conditioned animal room at 22°C and given tap water...
In order to evaluate a short-term carcinogenicity testing system using CB6F1 -Tg rasH2 (rasH2-Tg) mice carrying a human prototype c-Ha-ras gene, 26-week studies were conducted in 12 different facilities as a part of an International Life Science Institute Health and Environmental Science Institute (ILSI HESI) international collaborative project. In each study N-methyl-N-nitrosourea (MNU) was administered to a separate group of rasH2-Tg mice by single intraperitoneal injection (75 mg/kg) as a positive control. We herein have summarized the mortality, body weight change, and neoplastic and nonneoplastic lesions detected in these positive control groups as representative historical positive control data. Also, we performed an interlaboratory comparison of the response of rasH2-Tg mice to MNU based on the data of 11 positive control groups from these studies. Although the body weight of rasH2-Tg mice showed lower values than that of non-Tgmice during the experimental period, body weight gain in the rasH2-Tg mice was similar to that in non-Tg mice. The mortality of rasH2-Tg mice during the study period was very low, the same as for the non-Tg mice. Incidences of spontaneous alveolar/bronchiolar adenomas and splenic hemangiomas/hemangiosarcomas were also low in the rasH2-Tg mice. Nonneoplastic lesions detected in the rasH2-Tg mice were similar to those in non-Tg mice, excluding the incidence of myopathy. There were interlaboratory differences in mortality and incidence of some lesions in the MNU-treated groups. However, the causes of death were common among the 11 laboratories and almost all the MNU-treated rasH2-Tg mice developed forestomach squamous cell papillomas/carcinomas or malignant lymphomas. This suggests that there is no appreciable difference in the response of the rasH2-Tg mouse to MNU used as a positive control. Therefore, it is concluded that MNU would be an adequate positive control compound in this testing system.
The influence of the level of carcinogen exposure on histopathological types and cellular differentiation of the induced tumors was examined in 100 male BALB/c mice given N-methyl-Nnitrosourea (MNU) in their drinking water at 240 ppm on alternate weeks (total exposure: five weeks) (group 1), at 120 ppm similarly (total exposure: ten weeks) (group 2), at 60 ppm for 20 weeks continuously (group 3), or at 30 ppm for 40 weeks continuously (group 4). Forty-three differentiated and 17 undifferentiated type adenocarcinomas were induced. Glandular stomach carcinomas and undifferentiated type lesions were more common in mice treated with a high concentration of MNU for a short period than with a low concentration of MNU for a long period, even though total measured intake of MNU was smaller (P< < < <0.01). All the induced glandular stomach carcinomas, independent of the treatment schedule, consisted entirely of gastric phenotype cells. In conclusion, the induction of glandular stomach cancers and the proportion of undifferentiated type lesions depend not on the total quantity, but rather on the concentration of the carcinogen, while the phenotypic expression of tumor cells is not affected by the differences in the administration protocol.
The potent role of indigenous microbiota in maintaining murine CMV (MCMV)-specific memory T cells, which were measured by multimer staining, was investigated using germfree (GF) mice. When the BALB/c mice bred under specific pathogen-free (SPF) conditions were i.p. infected with 0.2 LD50 of MCMV, high frequencies of CD69+/CD44+ MCMV-specific CD8 T cells were noted in the lungs even at 6–12 mo after infection (11.1 ± 3.2 and 9.8 ± 0.9%, respectively). In contrast, even though the viral load and expression levels of mRNA of such cytokines as IL-2, IL-7, IL-15, and IFN-γ in the lungs of MCMV-infected GF mice were comparable to those of infected SPF mice, the frequencies of MCMV-specific CD8 T cells in the lungs of infected GF mice were kept lower than 1% at 6–12 mo after infection. In addition, the reconstitution of microbiota of MCMV-infected GF mice by orally administering a fecal suspension prepared from SPF mice restored the frequencies of both CD8+/multimer+ and CD8+/multimer− T cells to levels similar to those found in SPF mice. These results suggested the indigenous microbiota to play a crucial role in the expansion and maintenance of viral-specific CD8 memory T cells, probably by cross-reactivity between the antigenic epitope of the MCMV-specific memory T cells and the variety of peptides derived from the members of the microbiota. Such cross-reactivity may thus be a major feature of those cells.
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