Research News

Cleveland Clinic researchers have uncovered how COVID-19 infection triggers severe inflammation, leading to long-term bone pain and bone loss. This research provides critical insights into the estimated 18 million individuals living with “COVID bone pain” worldwide.  

The JCI Insight study also reveals why individuals living with inflammatory autoimmune diseases, such as rheumatoid arthritis, report higher levels of bone pain after contracting COVID-19. The virus-induced inflammation disproportionately affects individuals with preexisting inflammatory autoimmune conditions, amplifying the severity of bone-related symptoms.  

How are rheumatoid arthritis, long COVID and bone pain connected? 

Up to 25% of individuals living with long COVID-19 report bone-related symptoms, including bone pain and density loss, persisting for months after their initial infection, says study co-lead author Javier Chen, PhD.   

Many of these patients have preexisting immune-mediated inflammatory diseases like Crohn’s disease, lupus or rheumatoid arthritis. For these individuals, the compounding effects of COVID-19 can lead to significant bone mineral density (BMD) loss, which greatly increases the risk of fractures from minor injuries and of progression to osteoporosis in severe cases. 

“Chronic inflammation itself significantly disrupts bone metabolism, accelerating density loss and impairing the body’s ability to build new bone tissue,” says Dr. Chen. “For patients with rheumatoid arthritis, even a moderate COVID-19-related bone loss might exacerbate an already compromised skeletal system.” 

What role does the immune system play in COVID-associated bone pain? 

Dr. Chen, a pioneer in the field of osteovirology - the study of how viruses affect bone health - led this groundbreaking research. His team aimed to understand how SARS-CoV-2 virus causes bone pain and bone loss, particularly in individuals living with inflammatory autoimmune diseases. 

“SARS-CoV-2 has introduced long-term complications that continue to affect people years after infection,” says study co-first author Ivonne Melano, PhD, a postdoctoral fellow in Dr. Chen’s lab. “We’ve only begun to uncover the mechanisms behind these complications.” 

Dr. Chen, Dr. Melano and co-first author Tamiris Azamor, a former postdoc from the Foo Lab, teamed up with study co-lead author Jolin Foo, PhD, who leads a virology lab in the Infection Biology Program; as well as with Cleveland Clinic’s Florida Research & Innovation Center (FRIC) and the Cleveland Clinic BioRepository (CC-BioR).  

They formed a multidisciplinary team that included experts from the Cleveland Clinic’s Department of Orthopaedic Surgery and the Department of Rheumatologic and Immunologic Disease. The CC-BioR provided plasma samples for proteomic analysis. 

Through their analysis, the team found that individuals with preexisting inflammatory autoimmune disorders and COVID-19 had elevated levels of proteins involved in producing osteoclasts, cells responsible for breaking down bone tissue. They also found increased levels of a SARS-CoV-2 protein called ORF8. Previous research from Cleveland Clinic had shown that ORF8 triggers harmful inflammation during SARS-CoV-2 infection.  

How does ORF8 contribute to bone pain in patients with autoimmune conditions? 

To explore the impact of ORF8, the team worked with orthopaedic surgeon Nicolas Piuzzi, MD, to obtain cells that make bone tissue called osteoblasts, which were donated by healthy individuals and individuals with rheumatoid arthritis.  

The team first treated the osteoblasts with ORF8 to mimic an active infection. After the osteoblasts had time to react to the treatment and release new molecules into their environment, the team removed the liquid medium the osteoblasts grew in and used it to treat bone marrow macrophages with the goal of seeing how infected osteoblasts impact other cells.  

While ORF8 had little effect on healthy bone cells, it strongly activated rheumatoid arthritis bone cells. The viral protein caused RA-affected osteoblasts to release inflammatory signals that transformed bone marrow macrophages into bone-dissolving osteoclasts, potentially accelerating bone breakdown. 

“This research supports the hypothesis that ORF8 drives inflammation in rheumatoid arthritis patients, causing their immune systems to mistakenly produce osteoclasts that break down healthy bone, perceiving it as damaged due to inflammation,” explains Dr. Chen. “This leads to the unnecessary production of osteoclasts, intensifying bone pain and density loss.”  

This discovery lays the groundwork for exploring strategies to mitigate ORF8-induced inflammation, with the ultimate goal of preventing bone pain and loss. 

“There's so much to uncover now that we have identified a mechanism, and we are exploring different immune-mediated inflammatory diseases to better understand how viral mechanisms may contribute to bone pain”, Dr. Chen says. “Although the ultimate goal of eliminating bone pain may seem idealistic, we will do everything we can to turn that ideal into reality.”