Rapamycin-induced hyperglycemia is associated with exacerbated age-related osteoarthritis

Abstract

Background The objective of this study was to determine if mechanistic target of rapamycin (mTOR) inhibition with or without AMP-activated protein kinase (AMPK) activation can protect against primary, age-related OA. Design Dunkin-Hartley guinea pigs develop mild primary OA pathology by 5 months of age that progresses to moderate OA by 8 months of age. At 5 months, guinea pigs served as young control (n = 3) or were fed either a control diet (n = 8), a diet enriched with the mTOR-inhibitor rapamycin (Rap, 14 ppm, n = 8), or Rap with the AMPK-activator metformin (Rap+Met, 1000 ppm, n = 8) for 12 weeks. Knee joints were evaluated by OARSI scoring, micro-computed tomography, and immunohistochemistry. Glenohumeral articular cartilage was collected for western blotting. Results Rap- and Rap+Met-treated guinea pigs displayed lower body weight than control. Rap and Rap+Met inhibited articular cartilage mTORC1 but not mTORC2 signaling. Rap+Met, but not Rap alone, stimulated AMPK. Despite lower body weight and articular cartilage mTORC1 inhibition, Rap- and Rap+Met-treated guinea pigs had greater OA severity in the medial tibial plateau due to articular cartilage structural damage and/or proteoglycan loss. Rap and Rap+Met increased plasma glucose compared to control. Plasma glucose concentration was positively correlated with proteoglycan loss, suggesting hyperglycemic stress after Rap treatment was related to worsened OA. Conclusions This is the first study to show that Rap induced increase in plasma glucose was associated with greater OA severity. Further, articular cartilage mTORC1 inhibition and bodyweight reduction by dietary Rap and Rap+Met did not appear to protect against primary OA during the prevailing hyperglycemia.

Rat synovial tissue and blood rapamycin pharmacokinetics after intra-articular injection of free solution or nanoparticles vs free rapamycin intravenous shot

“…Thus, local and systemic administration of rapamycin in rodent osteoarthritic models decreases chondral lesions (Liu et al, 2020;Matsuzaki et al, 2014;Takayama et al, 2014;Xu et al, 2019). However, rapamycin's numerous biological side effects cause undesirable systemic and paradoxical off-target articular adverse consequences, like reducing bone thickness, when administered systemically (Minton et al, 2021). It induces lipid and carbohydrate dysmetabolism and hematological disorders (anemia, thrombocytopenia), which may increase morbidity and mortality in patients suffering from systemic diseases more severe than osteoarthritic related pain (Nguyen et al, 2019).…”

Correction to: Rapamycin-induced hyperglycemia is associated with exacerbated age-related osteoarthritis

“…Following publication of the original article [ 1 ], the authors reported a spelling error in the fourth author’s last name. Author Kelly S. Santangelo has been corrected.…”