Nicotinamide Riboside Counteracts Osteoarthritis Through Preserving Mitochondrial Unfolding Response

Mitochondrial dysfunction results extracellular matrix underproduction in chondrocytes, accelerating osteoarthritic degeneration. Mitochondrial unfolding response (UPRmt) plays an important role in maintaining proteostatsis to keep mitochondrial microenvironment away from unfolded protein toxicity caused by extracellular stress. Dysregulated UPRmt is found to promote senescence, oxidative stress, and tissue dysfunction. We investigate whether control of UPRmt by nicotinamide riboside (NR) affects chondrocyte anabolism and osteoarthritis development. Inflamed chondrocytes as an in vitro model of OA induced IL-1b are incubated with NR. Expression of chondrocyte markers (Acan, Col2, SOX9) and key UPRmt markers (ClpP, Lonp1, Hsp10, Atf5, and Hsp60), and glycosaminoglycan production are measured using RT-PCR and Alcian blue stain. Cartilage-specific Hsp60 knockout is used to evaluate cartilage integrity. NR is intra-articularly injected into destabilized medial meniscus (DMM)-induced knee injury. Articular cartilage damage, osteophyte formation, and gait profiles of injured legs are measured using OARSI score, micro-CT imaging, and Catwalk. Extracellular matrix glycosaminoglycan underproduction is correlated with UPRmt loss and decreased mitophagosome formation in inflamed chondrocytes. NR supplementation improving Hsp60, Lonp1, and Atf5 expression, mitigating inflammation-induced oxidative stress, and glycosaminoglycan loss. Cartilage-specific Hsp60 knockout mice exhibit a phenotype of relatively thin articular cartilage as compared to wild-type mice. Hsp60 deletion exacerbates age- and DMM-induced OA-like signs, including cartilage damage, synovial hyperplasia and osteophyte formation. Notably, intra-articular injection with NR attenuates Hsp60 loss- and DMM-induced OA features, including cartilage loss, synovitis, osteophyte formation and irregular walking patterns. Collective findings shed light to the chondroprotective actions of UPRmt to chondrocytic activity. Hsp60, a key UPRmt chaperonin, is indispensable to maintain cartilage homeostasis, and its loss accelerates osteoarthritic degeneration. We also highlight the remedial potential of NR for slowing OA development.