Aromatase-Inhibitor-Induced Musculoskeletal Inflammation Is Observed Independent of Oophorectomy in a Novel Mouse Model.

Aromatase Inhibitors (AIs) block estrogen production and improve survival in patients with hormone-receptor-positive breast cancer. However, half of patients develop aromatase-inhibitor-induced arthralgia (AIIA), which is characterized by inflammation of the joints and the surrounding musculoskeletal tissue. To create a platform for future interventional strategies, our objective was to characterize a novel animal model of AIIA. Female BALB/C-Tg(NFκB-RE-luc)-Xen mice, which have a firefly luciferase NFκB reporter gene, were oophorectomized and treated with an AI (letrozole). Bioluminescent imaging showed significantly enhanced NFκB activation with AI treatment in the hind limbs. Moreover, an analysis of the knee joints and legs via MRI showed enhanced signal detection in the joint space and the surrounding tissue. Surprisingly, the responses observed with AI treatment were independent of oophorectomy, indicating that inflammation is not mediated by physiological estrogen levels. Histopathological and pro-inflammatory cytokine analyses further demonstrated the same trend, as tenosynovitis and musculoskeletal infiltrates were detected in all mice receiving AI, and serum cytokines were significantly upregulated. Human PBMCs treated with letrozole/estrogen combinations did not demonstrate an AI-specific gene expression pattern, suggesting AIIA-mediated pathogenesis through other cell types. Collectively, these data identify an AI-induced stimulation of disease pathology and suggest that AIIA pathogenesis may not be mediated by estrogen deficiency, as previously hypothesized.

Operant task performance and corticosterone concentrations in rats housed directly on bedding and on wire.

The present experiment was designed to investigate the effect of housing conditions on task performance and corticosterone response. Two groups of male F344BNF1 rats were housed on a ventilated rack with ad libitum access to water and a restricted feeding regime. Group 1 was housed in solid-bottom caging with corn cob bedding, whereas group 2 was housed in wire-bottom caging. After learning an operant task, each rat was exposed to acute restraint followed 48 h later by exposure to continuous light. Corticosterone concentrations were determined before and after exposure to each intervention. Contrary to assumptions, housing did not affect task performance. Baseline corticosterone concentrations were similar for the 2 experimental groups, but corticosterone concentrations were significantly higher for the wire-bottom group than the solid-bottom group immediately after the restraint and remained elevated 2 d later. Corticosterone levels decreased in both groups after exposure to continuous light. Overall, the data indicate that subtle but significant differences occur in responses of rats housed on wire-bottom versus solid-bottom caging when the animals are exposed to acute restraint.

Coping strategies in male and female rats exposed to multiple stressors.

Because of the pathogenic effects of chronic stress exposure, it is important to identify factors, such as effective coping strategies, that mitigate stress-induced pathology. Of interest in the present study was the consistency of behavioral responses across a diverse array of stressors. Sixteen male and 16 female Long-Evans rats were assigned to either a stress or control group. The stressed animals were subsequently exposed to a battery of ecologically relevant stressors (e.g., predator odor, novel stimuli, and immunological challenge) to determine trends in coping strategies. Blood was collected for corticosterone (CORT) assay and brains were harvested for assessment of fos immunoreactivity in the paraventricular hypothalamus (PVH) and central amygdala (CEA) following exposure to the final stressor of fox urine. A correlational analysis indicated that certain response strategies (e.g., latency to respond in different stress tests such as the open-field and novel item tests) persist across several behavioral tests, especially those tests involving exploratory components. A subsequent principal component factor analysis revealed the following four components: initiative to explore, low reactivity, variable reactivity, and high reactivity. Females exhibited higher recovery CORT levels than males; however, sex only affected one behavioral response measure (i.e., females demonstrated more attempts to climb the wall in the forced-swim test than their male counterparts). In conclusion, these results support the importance and prevalence of initiative to explore as a common factor in many stress tests; additionally, the principal component analysis indicated that physiological correlates of stress are more closely associated with more challenging environments and stimuli such as forced swimming, immunological challenges, and exposure to predator odors.