Blockade of endothelin receptors mitigates SARS-CoV-2-induced osteoarthritis
Open accessPublished version of a preprint
Abstract
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.
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In mice injected with viral spike receptor-binding domain, decreased paw withdrawal threshold and chronic pain-related secretion of substance P were reversed by the endothelin receptor blocker macitentan.
“Moreover, a decreased paw withdrawal threshold decrease was observed in mice injected with viral spike receptor-binding domain (RBD), and this hypersensitivity, as well as the chronic pain–related secretion of substance P (SP), could be successfully reversed by the endothelin receptor blocker macitentan (20).”
From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [20]
Cites
Jeon, O. H., Kim, C., Laberge, R.-M., Demaria, M., Rathod, S., Vasserot, A. P., Chung, J. W., Kim, D. H., Poon, Y., David, N., et al. (2017) · Nature Medicine · doi:10.1038/nm.4324 · Cited by 1,515 · cited 1× · see citing works
“Nuclear translocation of p16 INK4a is regarded as a typical characteristic of cellular senescence 36,37 .”
Evangelou, K., Veroutis, D., Paschalaki, K., Foukas, P. G., Lagopati, N., Dimitriou, M., Papaspyropoulos, A., Konda, B., Hazapis, O., Polyzou, A., et al. (2022) · European Respiratory Journal · doi:10.1183/13993003.02951-2021 · Cited by 98 · see citing works
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Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization
Lai, W., Tang, X., Chen, S., Zhou, Y., Qi, Z., Cao, M., Yuan, C., Yu, J., & Wen, C. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1677310 · Cited by 4 · see citing works
“…paw withdrawal threshold decrease was observed in mice injected with viral spike receptor-binding domain (RBD), and this hypersensitivity, as well as the chronic pain – related secretion of substance P (SP), could be successfully reversed by the endothelin receptor blocker macitentan (20).”
Self-citation
- Authors
- Au, M. T., Ni, J., Tang, K., Wang, W., Zhang, L., Wang, H., Zhao, F., Li, Z., Luo, P., Lau, L. C.-M., Chan, P.-K., Luo, C., Zhou, B., Zhu, L., Zhang, C. Y., Jiang, T., Lauwers, M., Chan, J. F.-W., Yuan, S., & Wen, C.
- Affiliations
- Hong Kong Polytechnic University (HK)
- University of Hong Kong (HK)
- Southern University of Science and Technology (CN)
- Hong Kong Baptist University (HK)
- Hong Kong Science and Technology Parks Corporation (HK)
- Corresponding author
- Yuan, Shuofeng
- Wen, Chunyi
- ORCID
- Venue
- Nature Microbiology
- Published
- 2024-09-11
- Volume
- 9
- Issue
- 10
- Pages
- 2538-2552
- ISSN
- 2058-5276 (ISSN-L)
- OpenAlex
- W4402459574
- Cited by
- 11
- References
- 2
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 1
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-09-16)
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Microbiology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion, cc-by-nc-nd)
- Funders
- National Natural Science Foundation of China (32300134, 32322087)
- Innovation and Technology Commission
- Hong Kong Polytechnic University
- Food and Health Bureau (16172691, COVID-19, 07210107, CID-HKU1-11)
- Health and Medical Research Fund (CID-HKU1, 16172691)
- Sanming Project of Medicine in Shenzhen (SZSM201911014)
- National Key Research and Development Program of China (2020YFA0707504, 2020YFA0707500, 2020YFA0707500 and 2020YFA0707504, 2021YFC0866100)
- Northwest Fisheries Science Center
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone and Joint Diseases
- Keywords
- SARS-CoV-2, endothelin-1, endothelin receptor antagonists, macitentan, articular cartilage damage, chondrocyte senescence, osteoclast activation, subchondral bone loss, joint pain, spike protein, cystic lesions, post-COVID-19 sequelae
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Animals, Cartilage, Articular, Disease Models, Animal, Female, Cricetinae, Humans, Male, Mesocricetus, Osteoarthritis, Pyrimidines, Sulfonamides, Receptors, Endothelin, Endothelin-1, Chondrocytes, Spike Glycoprotein, Coronavirus, Endothelin Receptor Antagonists
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