The Hidden Toll of COVID: Your Joints Are at Risk!

The Hidden Toll of COVID: Your Joints Are at Risk!
Like

Share this post

Choose a social network to share with, or copy the URL to share elsewhere

This is a representation of how your post may appear on social media. The actual post will vary between social networks

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 symptoms1,2. Without timely intervention, around 10% of them eventually developed debilitating long COVID syndrome at one year post-infection2,3. 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).

A, 3D reconstruction of tibial plateau of knee joints; the arrow indicates the collapse of the medial tibial plateau. OA, osteoarthritis. B, 3D volume-rendered CT images showing the vessel distribution at the skin level; arrows indicate bulging or twisted vessels. Scale bars, 1 cm.

Rapid joint destruction in patients with COVID|A, 3D reconstruction of tibial plateau of knee joints; the arrow indicates the collapse of the medial tibial plateau. OA, osteoarthritis. B, 3D volume-rendered CT images showing the vessel distribution at the skin level; arrows indicate bulging or twisted vessels. Scale bars, 1 cm.

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

While this study provides valuable insights into the detrimental effect of SAR-CoV-2 infection on bone and cartilage, it is limited to clinical case report and animal study. More analyses are required in a large scale clinical cohort to understand the impact of SARS-CoV-2 viral spike on chondropathy.

Reference

1          Nalbandian, A. et al. Post-acute COVID-19 syndrome. Nat Med 27, 601-615, doi:10.1038/s41591-021-01283-z (2021).
2          Heesakkers, H. et al. Clinical Outcomes Among Patients With 1-Year Survival Following Intensive Care Unit Treatment for COVID-19. JAMA 327, 559-565, doi:10.1001/jama.2022.0040 (2022).
3          Group, P.-C. C. Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study. Lancet Respir Med 10, 761-775, doi:10.1016/S2213-2600(22)00127-8 (2022).
4          Bowe, B., Xie, Y. & Al-Aly, Z. Postacute sequelae of COVID-19 at 2 years. Nat Med, doi:10.1038/s41591-023-02521-2 (2023).
5          Fan, B. E. et al. Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long-term outcomes in COVID-19 patients. Am J Hematol 97, 915-923, doi:10.1002/ajh.26575 (2022).
6          Abraham, G. R. et al. Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19. J Mol Cell Cardiol 167, 92-96, doi:10.1016/j.yjmcc.2022.03.007 (2022).
7          Zhao, Z., Li, E., Cao, Q., Sun, J. & Ma, B. Endothelin-1 concentrations are correlated with the severity of knee osteoarthritis. J Investig Med 64, 872-874, doi:10.1136/jim-2015-000030 (2016).
8          De-Melo, J. D., Tonussi, C. R., D'Orleans-Juste, P. & Rae, G. A. Articular nociception induced by endothelin-1, carrageenan and LPS in naive and previously inflamed knee-joints in the rat: inhibition by endothelin receptor antagonists. Pain 77, 261-269, doi:10.1016/S0304-3959(98)00098-0 (1998).
9          Zuo, W. et al. The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in China. Lancet Infect Dis 24, 845-855, doi:10.1016/S1473-3099(24)00171-3 (2024).

Please sign in or register for FREE

If you are a registered user on Research Communities by Springer Nature, please sign in

Follow the Topic

COVID19
Life Sciences > Health Sciences > Biomedical Research > Pathogenesis > Infection > Infectious Diseases > COVID19
Osteoarthritis
Life Sciences > Health Sciences > Clinical Medicine > Diseases > Rheumatic Diseases > Osteoarthritis
Microbiology
Life Sciences > Biological Sciences > Microbiology

Related Collections

With collections, you can get published faster and increase your visibility.

Progress towards the Sustainable Development Goals

The year 2023 marks the mid-point of the 15-year period envisaged to achieve the Sustainable Development Goals, targets for global development adopted in September 2015 by all United Nations Member States.

Publishing Model: Hybrid

Deadline: Ongoing