Blockade of endothelin receptors mitigates SARS-CoV-2-induced osteoarthritis

• DOI: 10.1038/s41564-024-01802-x
• Publication Date: 2024-09-11T10:04:36Z
• Authors: Man Ting Au; Junguo Ni; Kaiming Tang; Wei Wang; Lanlan Zhang; Hantang Wang; Fangyi Zhao; Zhan Li; Peng Luo; Lawrence Chun-Man...; Ping-Keung Chan; Cuiting Luo; Bo Zhou; Lin Zhu; Charlie Yuli Zhang; Tianshu Jiang; Marianne Lauwers; Jasper Fuk-Woo Chan; Shuofeng Yuan; Chunyi Wen
• Keywords: Endothelin Receptor Antagonists; Male; Cartilage, Articular; Sulfonamides; Mesocricetus; Endothelin-1; SARS-CoV-2; Receptors, Endothelin; COVID-19; COVID-19 Drug Treatment; Disease Models, Animal; Pyrimidines; Chondrocytes; Cricetinae; Osteoarthritis; Spike Glycoprotein, Coronavirus; Animals; Humans; Female

Joint pain and osteoarthritis can occur as coronavirus disease 2019 (COVID-19) sequelae after infection. However, little is known about the damage to articular cartilage. Here we illustrate knee joint damage after wild-type, Delta and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vivo. Rapid joint injury with cystic lesions at the osteochondral junction was observed in two patients with post-COVID osteoarthritis and recapitulated in a golden Syrian hamster model. SARS-CoV-2-activated endothelin-1 signalling increased vascular permeability and caused viral spike proteins leakage into the subchondral bone. Osteoclast activation, chondrocyte dropout and cyst formation were confirmed histologically. The US Food and Drug Administration-approved endothelin receptor antagonist, macitentan, mitigated cystic lesions and preserved chondrocyte number in the acute phase of viral infection in hamsters. Delayed macitentan treatment at post-acute infection phase alleviated chondrocyte senescence and restored subchondral bone loss. It is worth noting that it could also attenuate viral spike-induced joint pain. Our work suggests endothelin receptor blockade as a novel therapeutic strategy for post-COVID arthritis.