Objective. To characterize the clinical and histopathologic changes in a rat model of broad-spectrum matrix metalloproteinase (MMP)-induced musculoskeletal syndrome (MSS), and to facilitate research into the causes and treatments of MSS in humans.Methods. Male Lewis rats weighing 150-180 gm were administered 10-30 mg of the broad-spectrum MMP inhibitor marimastat over a 2-week period via surgically implanted subcutaneous osmotic pumps. The animals were monitored and scored for the onset and severity of MSS, using clinical and histologic parameters.Results. Marimastat-treated rats exhibited various clinical signs, including compromised ability to rest on their hind feet, high-stepping gait, reluctance or inability to move, and hind paw swelling. Histologically, marimastat-treated rat joints were characterized by soft tissue and bone changes, such as increased epiphyseal growth plate, synovial hyperplasia, and increased cellularity in the joint capsule and extracapsular ligaments. The severity of MSS, as judged by clinical criteria (2 blinded observers using 3 clinical parameters), paw volume, and histologic score, was nearly identical. The observed changes were indistinguishable from those reported for primate models and mimic MSS in humans.Conclusion. This simple and sensitive model of MSS is an attractive alternative for studying the pathology of MSS.
Gene transfer to chondrocytes followed by intra-articular transplantation may allow for functional modulation of chondrocyte biology and enhanced repair of damaged articular cartilage. We chose to examine the loss of chondrocytes transduced with a recombinant adenovirus containing the gene for Escherichia coli beta-galactosidase (Ad.RSVntlacZ), followed by transplantation into deep and shallow articular cartilage defects using New Zealand White rabbits as an animal model. A type I collagen matrix was used as a carrier for the growth of the transduced chondrocytes and to retain the cells within the surgically created articular defects. Histochemical analysis of matrices recovered from the animals 1, 3 and 10 days after implantation showed the continued loss of lacZ positive chondrocytes. The number of cells recovered from the matrices was also compared with the initial innoculum of transduced cells present within the matrices at the time of implantation. The greatest loss of transduced cells was observed in the first 24 h after implantation. The numbers of transduced cells present within the matrices were relatively constant between 1 and 3 days postimplantation, but had progressively declined by 10 days postimplantation. These results suggest that transduction of chondrocytes followed by intra-articular transplantation in this rabbit model may enable us to examine the biological effects of focal transgenic overexpression of proteins involved in cartilage homeostasis and repair.
DNAs from 19 malignant human breast tumors and 2 benign fibroadenomas were analyzed for heterozygosity at 5 polymorphic loci on the short arm of chromosome 3. One homozygous deletion and one rearrangement were identified using probe D3S2 which maps to 3p14.3-3p21.1. This probe also detected novel hybridizing fragments of 2.0 kb and/or 3.4 kb in 6/18 (33%) of the malignant tumor samples that hybridized with the D3S2 probe following digestion with the 5'-methylcytosine-insensitive enzyme MspI. Comparisons of HpaII and MspI digestion showed that all but one of the tumor DNAs analyzed were hypermethylated. The two fibroadenoma DNAs were not as highly methylated and had hybridizing fragments of 3.4 kb after HpaII digestion. These malignant breast-tumor DNAs exhibit 3 mechanisms by which a tumor-suppressor gene hypothesized to reside at 3p14-3p21 could be inactivated: homozygous deletion, rearrangement and hypermethylation, and strongly implicate this 3p chromosome region in breast-tumor development.
Drug-induced liver injury (DILI) represents a leading cause of acute liver failure. Although DILI can be discovered in preclinical animal toxicology studies and/or early clinical trials, some human DILI reactions, termed idiosyncratic DILI (IDILI), are less predictable, occur in a small number of individuals, and do not follow a clear dose-response relationship. The emergence of IDILI poses a critical health challenge for patients and a financial challenge for the pharmaceutical industry. Understanding the cellular and molecular mechanisms underlying IDILI is key to the development of models that can assess potential IDILI risk. This study used Reverse Causal Reasoning (RCR), a method to assess activation of molecular signaling pathways, on gene expression data from rats treated with IDILI or pharmacologic/chemical comparators (NON-DILI) at the maximum tolerated dose to identify mechanistic pathways underlying IDILI. Detailed molecular networks involved in mitochondrial injury, inflammation, and endoplasmic reticulum (ER) stress were found in response to IDILI drugs but not negative controls (NON-DILI). In vitro assays assessing mitochondrial or ER function confirmed the effect of IDILI compounds on these systems. Together our work suggests that using gene expression data can aid in understanding mechanisms underlying IDILI and can guide in vitro screening for IDILI. Specifically, RCR should be considered for compounds that do not show evidence of DILI in preclinical animal studies positive for mitochondrial dysfunction and ER stress assays, especially when the therapeutic index toward projected human maximum drug plasma concentration is low.
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