SARS-CoV-2 ORF8 drives osteoclastogenesis in preexisting immune-mediated inflammatory diseases
Patients with immune-mediated inflammatory diseases (IMIDs) like rheumatoid arthritis (RA) are at higher risk for severe COVID-19 and long-term complications in bone health. Emerging clinical evidence demonstrated that SARS-CoV-2 infection reduces bone turnover and promotes bone loss, but the mechanism underlying worsened bone health remains elusive. This study sought to identify specific immune mediators that exacerbated preexisting IMIDs after SARS-CoV-2 exposure. Plasma samples from 4 groups were analyzed: healthy, IMID only, COVID-19 only, and COVID-19 + IMID. Using high-throughput multiplexed proteomics, we profiled 1,500 protein biomarkers and identified 148 unique biomarkers in COVID-19 patients with IMIDs, including elevated inflammatory cytokines (e.g., IL-17F) and bone resorption markers. Long-term circulating SARS-CoV-2 ORF8, a virulence factor for COVID-19, was detected in the COVID + IMID group. RA was one of the most common IMIDs in our study. ORF8 treatment of RA-derived human osteoblasts (RA-hOBs) increased levels of inflammatory (TNF, IL6, CCL2) and bone resorption (RANKL/osteoprotegerin ratio) markers compared with healthy controls. Supernatants from ORF8-treated RA-hOBs drove the differentiation of macrophages into osteoclast-like cells. These findings suggest that SARS-CoV-2 exposure can exacerbate IMIDs through ORF8-driven inflammation and osteoclastogenesis, highlighting potential therapeutic targets for managing COVID-19-induced bone pathologies.
Authors
- Tamiris Azamor
- Leonard H. Calabrese (ORCID: https://orcid.org/0000-0002-1789-4923)
- Cassandra Calabrese (ORCID: https://orcid.org/0000-0002-8773-7739)
- SUZY A. A. COMHAIR (ORCID: https://orcid.org/0000-0003-1918-9002)
- Gielenny M. Salem (ORCID: https://orcid.org/0000-0001-6077-1606)
- M. Elaine Husni (ORCID: https://orcid.org/0000-0002-3181-4205)
- Camila Carla da Silva Caetano (ORCID: https://orcid.org/0000-0002-9120-269X)
- Suan‐Sin Foo (ORCID: https://orcid.org/0009-0007-8174-0893)
- Karin Nielsen‐Saines (ORCID: https://orcid.org/0000-0002-1742-5211)
- Xianfang Wu (ORCID: https://orcid.org/0000-0002-2995-935X)
- Débora Familiar-Macedo (ORCID: https://orcid.org/0000-0002-9229-5912)
- Jae U. Jung (ORCID: https://orcid.org/0000-0003-4559-8774)
- Shuyang Chen (ORCID: https://orcid.org/0000-0002-7648-0771)
- Nicolas Santiago Piuzzi (ORCID: https://orcid.org/0000-0003-3007-7538)
- Ivonne Melano (ORCID: https://orcid.org/0000-0002-6057-9013)
- Youn Jung Choi (ORCID: https://orcid.org/0000-0001-6879-0115)
- Younho Choi (ORCID: https://orcid.org/0000-0003-4719-3279)
- Zilton Vasconcelos (ORCID: https://orcid.org/0000-0002-2193-2224)
- Brandy-Lee Soos
- Chineme Onwubueke (ORCID: https://orcid.org/0000-0002-3183-8266)
- Nikki M. Meyer
- Anabelle Visperas
- Weiqiang Chen (ORCID: https://orcid.org/0000-0002-8840-1823)
Institutions
- Cedars-Sinai Medical Center (US)
- Cleveland Clinic (US)
- University of California, Los Angeles (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Cleveland Clinic Florida (US)
- Fundação Oswaldo Cruz (BR)
Publication Details
- Journal
- JCI Insight
- Published
- 2024-12-19
- DOI
- https://doi.org/10.1172/jci.insight.178820
- Citations
- 3
- Primary Topic
- Osteomyelitis and Bone Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 1.41
Funders
- Cleveland Clinic
- National Institutes of Health
- Lerner Research Institute, Cleveland Clinic