Afzali, M. F. | Search bioRxiv

bioRxiv2022

Early removal of the infrapatellar fat pad pad beneficially alters the pathogenesis of moderate stage idiopathic knee osteoarthritis in the Dunkin Hartley guinea pig

BackgroundThe infrapatellar fat pad (IFP) is the largest adipose deposit in the knee; however, its contributions to the homeostasis of this organ remain unknown. To determine the influence of this depot on joint health, this study determined the progression of osteoarthritis (OA) following excision of the IFP in a rodent model of naturally-occurring disease. MethodsMale Dunkin-Hartley guinea pigs (n=10) received surgical removal of the IFP in one knee at 3 months of age; contralateral knees received sham surgery as matched internal controls. Treadmill-based gait analysis was performed prior to IFP removal and monthly thereafter. Animals were harvested at 7 months of age. Both knees were processed for microcomputed tomography (microCT), histopathology, transcript expression analyses, and immunohistochemistry (IHC). ResultsFibrous connective tissue (FCT) developed in place of the native fat pad. Gait demonstrated no significant differences between IFP removal and contralateral limbs. MicroCT OA scores were improved in knees with the FCT. Histopathology confirmed maintenance of articular cartilage structure, proteoglycan content, and chondrocyte cellularity in FCT-containing knees. Transcript analyses revealed decreased expression of adipose-related molecules and inflammatory mediators in FCTs compared to IFPs. This was corroborated via IHC for select inflammatory mediators. Discussion/ConclusionFormation of the FCT resulted in reduced OA-associated changes in both bone and cartilage. A decrease in inflammatory mediators at transcript and protein levels may be associated with these improvements. The IFP may therefore play a role in the pathogenesis of knee OA in this strain, with removal prior to disease onset appearing to have short-term benefits.

pathology↗

bioRxiv2021

Phytochemical Nrf2 activator attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a preclinical model of musculoskeletal aging

Musculoskeletal dysfunction is an age-related syndrome associated with impaired mitochondrial function and proteostasis. However, few interventions have tested targeting two drivers of musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that stimulates transcription of cytoprotective genes and improves mitochondrial function. We hypothesized daily treatment with a Nrf2 activator in Hartley guinea pigs, a model of age-related musculoskeletal dysfunction, attenuates the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis, preserving musculoskeletal function. We treated 2-month- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical Nrf2 activator PB125 (Nrf2a). Longitudinal assessments of voluntary mobility were measured using Any-Maze open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in permeabilized soleus muscles was measured using ex vivo high resolution respirometry. In both sexes, Nrf2a 1) increased electron transfer system capacity; 2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and 3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial, and cytosolic subfractions of the soleus. These improvements were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, these results demonstrate that treatment with an oral Nrf2 activator contributes to maintenance of skeletal muscle mitochondrial function and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these improvements are also accompanied by slowed progression of other aspects of musculoskeletal decline.

physiology↗