Abstract Objective The biologic changes associated with osteoarthritis (OA) are incompletely understood. The aim of this study was to elucidate the molecular mechanisms underlying OA progression in an STR/Ort murine model of spontaneous disease. Methods Global patterns of gene expression were assessed using microarray analysis of articular cartilage/subchondral bone from the tibial plateaus of STR/Ort mice at 3, 9, and 12 months of age. The age‐dependent severity of osteophyte formation and extent of cartilage damage were determined in the corresponding femurs using microfocal computed tomography and the Mankin histologic scoring system. Pathway analysis was used to identify the functions of genes associated with OA progression, and changes in gene expression were confirmed using immunohistochemistry. Results Six hundred twenty‐one genes were associated with both osteophyte formation and cartilage damage in the STR/Ort joints. Genes involved in the development/function of connective tissue and in lipid metabolism were most significantly enriched and regulated during disease progression. Genes directly interacting with peroxisome proliferator–activated receptor α (PPARα)/PPARγ were down‐regulated, whereas those genes involved with connective tissue remodeling were up‐regulated during disease progression. Associations of down‐regulation of myotubularin‐related phosphatase 1 (a phosphoinositide 3‐phosphatase involved in lipid signaling) and up‐regulation of biglycan (a member of the small leucine‐rich protein family known to modulate osteoblast differentiation and matrix mineralization) with OA progression were confirmed by immunohistochemistry. Conclusion Since adipogenesis and osteogenesis are inversely related in the developing skeletal tissue, these results suggest that a shift in the differentiation of mesenchymal cells from adipogenesis toward osteogenesis is a component of the OA pathophysiologic processes occurring in the tibial plateau joints of STR/Ort mice.
The primary enclosure of a laboratory animal's environment should encourage species-typical behavior and enhancement of the animal's well-being, as indicated by the Guide. Enrichment devices have been documented to decrease the incidence of stereotypical behaviors and increase overall activity of rabbits. An 8-week study was performed to evaluate the effect of an environmental enrichment device, stainless-steel rabbit rattles on spring clips, on individually housed rabbits in a Safety Assessment facility. We used 48 New Zealand White rabbits; the devices were placed on cages of 32 study rabbits, and 16 control rabbits had no devices. Food consumption measurements and observations of device manipulations (taken during a predetermined peak interaction 1-h timeframe) were collected 5 days per week. All rabbits were bled for evaluation of hematologic parameters for the stress triad (neutrophilia, lymphopenia, and eosinopenia) and weighed weekly. No significant differences were found between study and control rabbits when body weights, food consumption, and hematologic parameters were analyzed. Our study supports previous findings that interaction with enrichment devices decreases over time, thus indicating the need for frequent rotation of different enrichment devices. In addition, no adverse effects of the analyzed parameters were found, indicating that stainless-steel rabbit rattles on spring clips are suitable devices for safety assessment studies, in which the introduction of new variables is often unacceptable.
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