Osteoarthritis development in novel experimental mouse models induced by knee joint instability.

OBJECTIVE: Although osteoarthritis (OA) is induced by accumulated mechanical stress to joints, little is known about the underlying molecular mechanism. To apply approaches from mouse genomics, this study created experimental mouse OA models by producing instability in the knee joints. METHODS: The models were of four types: severe, moderate, mild, and medial, depending on the severity and direction of instability imposed by combinations of ligament transection and menisectomy. OA development was evaluated by X-ray and histology by Safranin-O staining, and quantified using our original gradings. Expressions of type II, IX and X collagens and matrix metalloproteinase (MMP)-2, -3, -9 and -13 were further examined by immunohistochemistry and in situ hybridization (ISH). RESULTS: The severe, moderate and mild models exhibited OA development in the posterior tibial cartilage. The severe model showed cartilage destruction at 2 weeks and osteophyte formation at 4-8 weeks after surgery; however, the mild model showed only a partial cartilage destruction at 8 weeks. The grading confirmed that the OA disorders progressed depending on the severity of joint instability. In the medial model, the OA development in the medial tibial cartilage was similar to that in the posterior cartilage of the mild model. Among the collagens and MMPs, type X collagen and MMP-13 were markedly induced and colocalized in the early stage OA cartilage. CONCLUSION: We established four types of mouse models exhibiting various speeds of OA progression. By applying a mouse genomics approach to the models, molecular backgrounds in various stages of OA development can be clarified.

Overexpression of cdk4/cyclin D1 induces apoptosis in PC12 cells in the presence of trophic support.

The induction of apoptosis by cell cycle regulator molecules under conditions optimal for exponential growth was examined in rat pheochromocytoma PC12 cells by overexpression of cyclins and cyclin-dependent kinases (cdks). By flow cytometry and by immunofluorescence, only cells overexpressing cdk4 or cyclin D1 underwent apoptosis, which was not associated with G1-arrest. Cdk4 kinase activity was significantly higher in cdk4-, or cyclin D1-expressing cells. Furthermore, induction of apoptosis by cdk4 was abrogated by co-transfection of p16(INK4), or dominant negative cdk4. These results suggest that upregulation of cdk4 kinase activity is a primary and critical mediator of apoptosis in PC12 cells under physiological conditions.

Involuted intraosseous lipoma of the sacrum showing high signal intensity on T1-weighted magnetic resonance imaging (MRI).

Involuted intraosseous lipoma with extensive fat necrosis resulting in cyst formation (Milgram stage III) is distinguishable from lesions without necrosis (stage I) or lesions with focal fat necrosis (stage II), based on differences in signal intensity on magnetic resonance imaging (MRI). Fat tissue has a high signal intensity on both T1- and T2-weighted MR images, whereas the extensive fat necrosis that results in cyst formation shows high signal intensity on T2-weighted images and low intensity on T1-weighted images. We report a patient in whom an intraosseous lipoma with high signal intensity on both T1- and T2-weighted MRI was found to be extensively involuted on histopathologic examination. Intraosseous lipoma appears to undergo spontaneous involution. In some patients, therefore, surgical excision may not be necessary. A correct preoperative diagnosis should reduce the necessity for a biopsy or surgery. Although lesions classified as stage I or II are easily identified by MRI, those of stage III are difficult to diagnose preoperatively by this method.