Blockade of Endothelin Receptors Mitigates SARS-CoV-2-induced Osteochondral Damage

Abstract Joint pain is a common post-acute COVID sequelae. Although pathological bone loss has been documented after SARS-CoV-2 infection, little is known about the damage to articular cartilage capping bone ends. Hereby, we characterise temporal changes of the bone-cartilage functional unit after SARS-CoV-2 infection in a golden Syrian hamster model. We observed cyst formation at osteochondral junction, chondrocyte senescence and subchondral bone loss in infected animals at 4 and 30 days post-infection. Endothelin signalling was upregulated with endothelial dysfunction and leakage of viral spike proteins to subchondral bone, triggering osteoclasts activation and chondrocytes senescence. Blockade of endothelin receptors using macitentan, an FDA-approved medication, alleviated cystic lesions and preserved chondrocyte number in acute phase of viral infection. Delayed macitentan treatment in post-acute infection phase still mitigated subchondral bone loss. Macitentan could also attenuate nociceptive pain induced by viral spike protein receptor binding domain injection in a mouse model. Collectively, macitentan is a repurposable drug candidate for treating SARS-CoV-2-induced joint damage and pain.