RIP3 Inhibition Slows the Progression of Osteoarthritis
RIP3 has been shown to be involved in system inflammatory signaling. Inhibition of its pathways or genetic deletion reduces the chronic inflammatory signaling of old age. Osteoarthritis is an inflammatory condition, and here researchers show that RIP3 is involved in the pathological loss of cartilage and alteration of bone tissue characteristic of the condition. They conclude that RIP3 is a good target for drugs to prevent or slow the progression of osteoarthritis.
Osteoarthritis (OA) is a debilitating joint disorder characterized by progressive cartilage degeneration. This study aims to investigate the role of receptor-interacting protein kinase-3 (RIP3) in OA progression, focusing on bone-cartilage metabolic homeostasis. RIP3-mediated pathological and metabolic alterations in chondrocytes, osteoblasts, and bone marrow-derived macrophages (BMMs) were evaluated. RIP3-mediated OA manifestations in cartilage and, more importantly, subchondral bone were determined by intra-articular overexpression of RIP3 in rats. The protective effect of RIP3 deficiency on the bone-cartilage unit during OA was systematically investigated using RIP3 knockout mice.
RIP3 was upregulated in the cartilage and subchondral bone of OA patients and post-traumatic OA mouse model. RIP3 overexpression not only inhibited extracellular matrix (ECM) anabolism in chondrocytes but also attenuated osteoblast differentiation, whereas RIP3 deficiency blunted receptor activator of NF-kappaB ligand-mediated osteoclastogenesis of BMMs. RIP3 deletion significantly improved structural outcomes of the bone-cartilage unit, and achieved pain relief as well as functional improvement in surgery-induced and spontaneous OA mouse models. Mechanistically, RIP3 initiates OA by perturbing critical events, including cartilage metabolism, inflammatory responses, senescence, and osteoclast differentiation. Clofibrate, a hypolipidemic drug, was identified as a novel RIP3 inhibitor that reverses ECM catabolism in OA.
In conclusion, RIP3 is an essential governor of whole joint metabolic homeostasis by regulating both cartilage metabolism and subchondral bone remodeling. Reconstruction of the bone-cartilage unit by targeting RIP3 might provide a two-birds-one-stone approach for the development of future OA therapies.