Oral Administration of a Chemically Modified Curcumin, TRB-N0224, Reduced Inflammatory Cytokines and Cartilage Erosion in a Rabbit ACL Transection Injury Model.

Abstract

To evaluate the effects of TRB-N0224, a chemically modified curcumin (CMC) with zinc binding properties and improved pharmacokinetics, in a rabbit anterior cruciate ligament (ACL) transection injury-induced model of osteoarthritis (OA). Thirty-eight skeletally mature New Zealand white rabbits were studied in 4 groups: a sham with arthrotomy (n = 6), control with ACL transection (n = 6), and 2 treatment groups with ACL transection and administration of TRB-N0224 at low (25 mg/kg/day) (n = 13) and high (50 mg/kg/day) (n = 13) doses. After euthanization at 12 weeks, outcomes were measured by post-necropsy gross morphology, biomechanics, and cartilage and synovium histology. Rabbit blood ELISA quantified cytokine and matrix metalloproteinase (MMP) concentrations at 0, 4, 8, and 12 weeks. Both treatment doses had fewer distal femoral condyle erosive defects than the control; the low dose demonstrated a mean 78% decrease (P < 0.01). Histologically, the low- and high-dose treatment groups had fewer cartilage pathologic changes and less severe synovitis than the control. CMC alone did not have a major effect on the biomechanics of healthy cartilage or cartilage in the ACL transection model, as demonstrated in 5 of the 6 measured properties/regions (P < 0.05). ELISA results suggested that the key mediators of OA, (interleukin) IL-1β, IL-6, TNFα (tumor necrosis factor-α), MMP-9, and MMP-13, had decreased concentrations with TRB-N0224 treatment at different time points between weeks 4 to 12 (P < 0.05). In the pathogenesis of OA, an imbalance exists between catabolic and anabolic mediators. These results suggest the potential of TRB-N0224 to modulate MMP and cytokine levels, slowing the macroscopic and histopathological progression of OA.