RESUMEN
BACKGROUND: Two strains of guinea pig develop spontaneous osteoarthritis of the knee. Although the disease evolves at different rates in the two strains, it is not known whether these differences are reflected in the structure of the cartilage and cancellous bone. QUESTIONS/PURPOSES: We determined whether the three-dimensional structure of the tibial-plateau cartilage and femoral cancellous bone differed between the two strains. METHODS: Six Dunkin-Hartley and six GOHI/SPF guinea pigs were evaluated. The animals were sacrificed at 11 months of age. The 24 proximal tibias were used for a stereologic histomorphometric analysis of the tibial-plateau cartilage. The 24 femurs were used for a site-specific, three-dimensional quantitative analysis of the cancellous bone by micro-CT. RESULTS: Compared to the GOHI/SPF guinea pigs, the tibial-plateau cartilage of the Dunkin-Hartley strain had a larger lesion volume (3.8% versus 1.5%) and a thicker uncalcified cartilage layer (0.042 versus 0.035 mm), but a thinner calcified cartilage zone (0.008 versus 0.01 mm) and a thinner subchondral cortical bone plate (0.035 versus 0.039 mm). The femoral cancellous bone in the Dunkin-Hartley strain had a lower bone mineral density (477 versus 509 mg/cm(3)). However, the trabeculae were thicker (3.91 versus 3.53 pixels) and farther apart (7.8 versus 5.6 pixels). The osteoarthritic changes in the cartilage were topographically mirrored in the subchondral bone. They were most severe on the medial side of the joint, particularly in the anterior region. CONCLUSIONS: Spontaneous osteoarthritis in the guinea pig is associated with site-specific changes in the articular cartilage layer, which are topographically mirrored in the underlying subchondral bone. CLINICAL RELEVANCE: Three-dimensional structural information not revealed by two-dimensional radiography may help characterize the stages of osteoarthritis.
Asunto(s)
Cartílago Articular/patología , Fémur/patología , Osteoartritis/patología , Tibia/patología , Animales , Densidad Ósea , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Fémur/diagnóstico por imagen , Cobayas , Miembro Posterior , Imagenología Tridimensional , Luz , Masculino , Microscopía/métodos , Osteoartritis/diagnóstico por imagen , Especificidad de la Especie , Microtomografía por Rayos XRESUMEN
OBJECTIVE: Collagen induced arthritis (CIA) is a model of chronic inflammatory synovitis with pannus, neovascularization, and joint destruction similar to rheumatoid arthritis (RA). Matrix metalloproteinases (MMP) are involved in degradation of the extracellular matrix and joint destruction in RA. c-fos and c-jun are protooncogenes whose products combine to form activating protein (AP-1), a regulatory protein that is required for cell proliferation and the transcription of a variety of genes, including MMP such as collagenase and stromelysin. Administration of vanadium compounds suppresses c-fos/c-jun expression and AP-1 activity, resulting in inhibition of MMP expression in response to factors such as interleukin 1 (IL-1). We evaluated whether a vanadium AP-1 inhibitor could reduce MMP expression and subsequent joint damage in CIA. METHODS: Vanadate [bis (maltolato) oxovanadium (IV) (BMOV; 10 mg/kg/day)] and the reducing agent N-acetyl cysteine (NAC; 100 mg/kg/day) were given subcutaneously daily in an attempt to suppress established CIA in rats. NAC in combination with vanadate appeared to increase the efficacy of c-fos/c-jun inhibition, while decreasing toxicity. Controls were given NAC alone. Clinical, radiographic, and histologic measures were evaluated as well as synovial MMP and IL-1a expression. RESULTS: BMOV therapy, initiated on the day of onset of clinical arthritis, significantly reduced clinical arthritis within 2 days (p <0.05) compared to controls. Significance was maintained to the termination of the study on Day 18 post-arthritis onset (p < 0.005), with a maximum difference seen on Day 5 (p < 0.00001). Blinded radiographic scores at the completion of the protocols indicated less joint destruction in the experimental group compared to the control group (p < 0.005). Scanning and transmission electron microscopy confirmed the preservation of articular cartilage with therapy. In BMOV-treated rats, synovial mRNA expression of collagenase, stromelysin, and IL-la were reduced by 78%, 58%, and 85%, respectively, compared to controls. CONCLUSION: This is the first study of vanadate as a potential antirheumatic agent. Further study of this AP-1 and MMP inhibitor may lead to new treatment options in RA.
Asunto(s)
Articulación del Tobillo , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Pironas/administración & dosificación , Vanadatos/farmacología , Acetilcisteína/administración & dosificación , Animales , Articulación del Tobillo/efectos de los fármacos , Articulación del Tobillo/patología , Artritis Experimental/patología , Colagenasas/efectos de los fármacos , Colagenasas/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Inyecciones Subcutáneas , Interleucina-1/metabolismo , Metaloproteinasa 3 de la Matriz/efectos de los fármacos , Metaloproteinasa 3 de la Matriz/metabolismo , Distribución Aleatoria , Ratas , Vanadatos/administración & dosificaciónRESUMEN
OBJECTIVE: Neurologic and psychiatric manifestations are severe complications of systemic lupus erythematosus (SLE). As commonly seen in patients, spontaneous development of lupus-like disease in MRL-lpr mice is accompanied by brain atrophy and behavioral dysfunction. We examined inflammatory and ultrastructural aspects of central nervous system (CNS) involvement using a nonselective cyclooxygenase-2 (COX-2) inhibitor and measuring effects on behavior, microglial activation, and neuronal morphology. METHODS: Ibuprofen (IBU) was provided in a rodent chow (375 ppm) for animals 5-19 weeks of age. Exploration of a novel environment and performance in the forced swim test assessed effects on behavior. Immunohistochemistry, fluoro-Jade B (FJB) staining, and flow cytometry were employed in neuropathological analysis. Transmission electron microscopy was used to examine ultrastructural morphology of cortical, hippocampal, hypothalamic, nigral, and cerebellar cells. RESULTS: Chronic IBU treatment failed to normalize immune status, behavior, and brain mass in lupus-prone MRL-lpr mice. It also did not reduce density of CD3+ lymphocytes in the choroid plexus, or FJB+ neurons in the hypothalamus. Activated F4/80+ microglia increased with age, but IBU treatment was not effective in reducing their numbers. Although numerous dark cells were seen in functionally critical brain regions (e.g., paraventricular nucleus and subgranular zone), ultrastructural morphologies of classical apoptosis or necrosis were not detected. CONCLUSION: The COX-dependent pathway does not seem to be critical in the etiology of CNS disease in this model of neuropsychiatric lupus. Reduced brain mass, increased microglial activation, and condensation of cytoplasm point to a metabolic perturbation (e.g., excitotoxic damage) that compromises function and survival of central neurons during lupus-like disease.