Thromboxane A2 receptor signalling amplifies osteoclastogenesis in rheumatoid arthritis through ACSL1 associated mitochondrial oxidative metabolism.

Activated platelets contribute to inflammation in rheumatoid arthritis, but how platelet-derived signals promote bone erosion remains poorly understood. Here we show that thromboxane A2, a major mediator released by activated platelets, promotes the formation of bone-resorbing osteoclasts through the thromboxane A2 receptor. Markers of thromboxane A2 biosynthesis are increased in patients with rheumatoid arthritis, while pharmacological inhibition or genetic loss of its receptor suppresses osteoclastogenesis in mouse cells and mice. Integrated molecular analyses reveal that thromboxane A2 receptor signalling supports osteoclastogenesis by increasing fatty acid oxidation and acetyl-coenzyme A supply needed for mitochondrial energy metabolism, involving peroxisome proliferator-activated receptor gamma coactivator 1 beta, peroxisome proliferator-activated receptor gamma and acyl-coenzyme A synthetase long-chain family member 1. In male mice, receptor inhibition or genetic deletion reduces osteoclast accumulation and bone destruction. These findings identify thromboxane A2 signalling as a driver of inflammatory bone erosion and a potential therapeutic target in rheumatoid arthritis.