COVID-19's Hidden Danger: Joint Damage

Musculoskeletal disorders are a major post-acute sequela of COVID-19, with arthralgia (joint pain) being one of the most persistent and debilitating symptoms^1,2. Without timely intervention, around 10% of them eventually developed debilitating long COVID syndrome at one year post-infection^2,3. Recently, osteoarthritis, for the first time to our best knowledge, has been identified as one of the post-acute sequelae that can persist for up to two years after SARS-CoV-2 infection⁴.

Impaired endothelial dysfunction has emerged to be a key contributor in COVID-19 progression and long COVID sequelae⁵. Elevated levels of plasma endothelin-1 (ET-1), the most potent vasoconstrictor, have been observed in hospitalised COVID patients⁶. ET-1 has been linked to joint damage⁷ and pain⁸, but its role in SARS-CoV-2-induced osteochondral damage remains unclear.

Our study and what we have done

This study was prompted by the disturbing trend of accelerated joint damage and intensified knee pain following SARS-CoV-2 infection. Two patients revealed severe pain and osteonecrosis-like changes in medial femoral condyle after contracting COVID-19 (Figure A), leading to unicompartmental knee arthroplasty (UKA) and were later diagnosed with osteoarthritis (OA). CT scans revealed vascular abnormalities around affected joints (Figure B).

To investigate the effect of infection on joint damage in vivo, we collaborated with Dr Shuofeng YUAN’s group from the University of Hong Kong to infect golden Syrian hamsters with different SARS-CoV-2 variants. The infected animals developed joint damage, including subchondral bone plate collapse and bulges. While meniscal extrusion was not obvious after infection, low-grade synovitis was observed in wild-type and Delta infection. Further analysis of wild-type SARS-CoV-2 infected hamsters showed persistent osteochondral damage, characterised by cartilage degradation, cyst formation, and upregulation of pain and senescence markers till one month post-infection.

Our study found that SARS-CoV-2-induced joint damage is accompanied by endothelial dysfunction, marked by increased oxidative stress, mitochondrial dysfunction and elevation of markers of endothelial damage - ET-1 and von Willebrand factor (vWF). A mouse model injected with SARS-CoV-2 spike receptor binding domain (RBD) showed hypersensitivity to pain, suggesting SARS-CoV-2 infection may result in chronic pain. We also discovered that spike protein, ET-1 or their combined effect increased permeability of blood vessels, allowing viral particles to leak to the surrounding joint tissue and leading to cartilage breakdown and premature ageing of chondrocytes. 

Our result suggested that endothelin receptor antagonism is effective in mitigating osteochondral damage and offering pain relief, both in early and delayed treatment. Macitentan reduced viral spike protein in the joint, thus alleviating cartilage damage and lowering the pain-related markers when administered one day post-infection. Delayed treatment after 2 weeks of infection still improved subchondral bone microstructure and reduced the senescence markers. Overall, macitentan treatment was found to be effective in alleviating SARS-CoV-2-induced osteoarthritis in both acute and sub-acute phase.

SARS-CoV-2-elicited joint pain is abiding and can implicate structural damage of the joint, which eventually develops into osteoarthritis. Using a mouse model, we found that spike protein alone triggers joint pain and induces chondrocyte senescence. Residual SARS-CoV-2 in the body was found positively associated with long COVID symptoms⁹. Our work highlights the importance of reducing viral spike uptake during the acute phase and suggests endothelin signalling as a therapeutic target for combating SARS-CoV-2-induced joint sequelae.

Future perspectives

Reference