Impact of long-term rapamycin treatment on age-related osteoarthritis in common marmoset

Abstract

AbstractObjectivePharmacologic inhibition of the mechanistic target of rapamycin (mTOR) can attenuate experimental osteoarthritis (OA) in young, male preclinical models. However, the potential of mTOR inhibition as a therapeutic mechanism for OA remains unknown. The goal of this study was to determine if mTOR-inhibition by oral rapamycin can modify OA pathology in the common marmoset, a translational model of age-associated OA.MethodsmicroCT and histopathologic assessments of the knee were performed on formalin-fixed hindlimbs obtained from common marmosets treated with oral rapamycin (n=24; 1mg/kg/day) or parallel control group (n=41). Rapamycin started at 9.2±3.0 years old and lasted until death (2.1±1.5 years). In a subset of marmosets, contralateral hind limbs were collected to determine mTOR signaling in several joint tissues.ResultsRapamycin decreased P-RPS6Ser235/36and increased P-Akt2Ser473in cartilage, meniscus, and infrapatellar fat pad, suggesting inhibition of mTORC1 but not mTORC2 signaling. Rapamycin-treated marmosets had lower lateral synovium score versus control but there was no difference in the age-related increase in microCT or cartilage OA scores. Subchondral bone thickness and thickness variability were not different with age but were lower in rapamycin-treated geriatric marmosets, which was largely driven by females. Rapamycin also tended to worsen age-related meniscus calcification in female marmosets.ConclusionOral rapamycin attenuated mTORC1 signaling and may have caused feedback activation of mTORC2 signaling in joint tissues. Despite modifying site-specific aspects of synovitis, rapamycin did not modify the age-associated increase in OA in geriatric marmosets. Conversely, rapamycin may have had deleterious effects on meniscus calcification and lateral tibia subchondral bone, primarily in geriatric female marmosets.