Letrozole Alters Transcriptomic Profiles in Infrapatellar Fat Pad From Female Mice: Possible Involvement of Interleukins in Aromatase Inhibitor‐Induced Arthralgias

ABSTRACT

Letrozole is an aromatase inhibitor (AIs) preventing estrogen synthesis from testosterone, and it induces many side effects, known as the aromatase inhibitor‐associated musculoskeletal syndrome (AIMSS), including arthralgias. However, its toxicity to the musculoskeletal system in female mice remains largely unknown. In this study, the mice were injected with letrozole subcutaneously for 12 weeks, and white cell count, pathological sectioning and RNA sequencing were used to investigate the effects of letrozole on the joint. Firstly, after the treatment of letrozole for 12 weeks, the mice with letrozole tended to gain weight and the number of white blood cells, lymphocytes and mean corpuscular hemoglobin concentration increased significantly by 88.2%, 87.4%, and 3.0% ( p  < 0.01), respectively. The hematocrit and platelet distribution width decreased by 6.2% and 1.7% ( p  < 0.05), respectively. Secondly, histopathological data revealed that the cartilage structure remained intact in both the control and letrozole groups, with no obvious signs of cartilage degradation. However, fibrosis of the infrapatellar fat pad (IFP) had dramatically increased at 12 weeks and the expression of ACAN and COL2A1 was significantly reduced, while ADAMTS5 and MMP13 were significantly increased. Thirdly, after the treatment of letrozole for 2 weeks, the differentially expressed genes in IFP were associated with the neutrophil‐mediated immunity and collagen degradation. Key inflammatory factors including IL‐1β, IL‐6, IL‐1A , and IL‐2 were identified as core targets. The effects of letrozole on transcriptomic profiles in IFP provided a new experimental basis for understanding the pathogenesis of AIMSS.