BREAKING! SARS-CoV-2 Targets Endothelin Receptors, Causing Bone And Cartilage Damage And Joint Pains. Endothelin Receptor Blocker Macitentan Helps

Macitentan sold under the brandname Opsumit can help in Long COVID manifestations of joint pains.
 
COVID-19 News: In a groundbreaking study conducted by researchers from The Hong Kong Polytechnic University, University of Hong Kong, and Hong Kong Baptist University, a significant breakthrough has been made in understanding the long-term effects of SARS-CoV-2 infection.
 
The study reveals that the virus can directly target endothelin receptors, leading to bone and cartilage damage, and subsequent joint pains. However, there is hope on the horizon, as an FDA-approved medication called macitentan has shown promising results in blocking these receptors and mitigating the damage caused by the virus.
 
One of the most common post-acute COVID-19 sequelae is joint pain, or arthralgia as reported in previous case series, studies and COVID-19 News reports. While the loss of bone mass after SARS-CoV-2 infection has been documented, little is known about the damage caused to the cartilage that covers the ends of bones. In this study, researchers used a golden Syrian hamster model to investigate the temporal changes in the bone-cartilage functional unit after SARS-CoV-2 infection. They discovered the formation of cysts at the osteochondral junction, senescence (cellular aging) of chondrocytes, and loss of subchondral bone in infected animals at 4- and 30-days post-infection.
 
The study team found that endothelin signaling, a pathway involved in the regulation of blood vessels, was upregulated following SARS-CoV-2 infection. This led to endothelial dysfunction and leakage of viral spike proteins into the subchondral bone, triggering the activation of osteoclasts (cells responsible for bone resorption) and senescence of chondrocytes. To counteract these effects, the researchers turned to macitentan, a medication approved by the FDA for the treatment of a different condition.
 
Remarkably, when macitentan was administered to infected animals, it alleviated cystic lesions and preserved the number of chondrocytes during the acute phase of viral infection. Even when treatment was delayed to the post-acute infection phase, macitentan still mitigated subchondral bone loss. Additionally, the medication was found to attenuate nociceptive pain induced by the viral spike protein receptor binding domain in a mouse model.
These findings have significant implications for the understanding and treatment of long COVID, particularly in relation to musculoskeletal complications.
 
Musculoskeletal disorders, including joint pain, have been observed in a considerable number of COVID-19 survivors. Without timely intervention, some individuals may develop debilitating long-term pain syndromes. Previous research has associated viral infections, including respiratory viruses, with an increased risk of inflammatory arthritis. Similarly, cases of viral arthralgia and inflammatory arthritis have been reported following SARS-CoV-2 infection.
 
Elevated levels of endothelin-1 (ET-1), a potent vasoconstrictor, have been detected in the plasma of hospitalized COVID-19 patients and correlated with the severity of joint damage. ET-1 has been shown to induce joint pain and cartilage degradation through its receptors, endothelin type A and B receptors (ETAR and ETBR). Animal studies have demonstrated that blocking endothelin receptors can have analgesic and chondroprotective effects in various arthritis models. Therefore, it is pla usible that the endothelin system plays a role in SARS-CoV-2-induced joint damage and pain.
 
The study team successfully replicated the pathological manifestations of acute SARS-CoV-2 infection in a golden Syrian hamster model and further investigated the damage caused by the virus to the articular cartilage. Their observations highlight the urgent need to screen COVID-19 survivors with persistent joint pain for structural damage. Public awareness of these long-haul skeletal complications is crucial, as early intervention is essential for successful treatment.
 
The exact mechanisms underlying virus-induced osteochondral damage or arthritis are still under investigation. It could result from direct viral insult, hyperinflammation, or autoimmune responses. The presence of viral RNA and proteins in joint tissues suggests a direct viral insult as a contributing factor.
 
Furthermore, the study demonstrated that elevated ET-1 levels, induced by SARS-CoV-2 exposure, could synergistically amplify the damage caused by the virus.

The study also shed light on the significant bone loss observed in long bones and vertebrae following SARS-CoV-2 infection. This bone loss may be attributed to cytokine storms and increased production of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta). In addition to these cytokines, ET-1, through its type A receptor, was found to stimulate osteoclastic activity and bone resorption. Targeting the endothelin type A receptor could be a potential therapeutic approach for mitigating SARS-CoV-2-induced subchondral bone loss.
 
The study also explored the role of cellular senescence in SARS-CoV-2-induced organ damage. Senescent cells, which undergo an irreversible growth arrest, have been implicated in COVID-19-related organ dysfunction. The researchers found that viral spike proteins and ET-1 can induce senescence in chondrocytes. Macitentan, with its dual blockade of endothelin type A and B receptors, was repurposed to protect the osteochondral junction in the knee joint from virus-induced damage.
 
In addition to its anti-inflammatory effects, macitentan has shown potential antiviral properties, as it has been reported to lower viral RNA counts in vitro. The researchers observed a decrease in viral spike protein levels in the joint tissues of infected hamsters following macitentan treatment. These experimental results are consistent with clinical observations, where patients with pulmonary hypertension treated with endothelin receptor antagonists, including macitentan, unexpectedly experienced recovery from SARS-CoV-2 pneumonia. Clinical trials are currently underway to explore the use of endothelin receptor antagonists in reducing multi-organ damage in COVID-19 patients.
 
While this study provides valuable insights into the mechanisms underlying SARS-CoV-2-induced joint damage and pain, there are a couple of limitations that should be considered. The study was conducted using young hamsters, and further research is needed to investigate osteochondral damage in aged hamsters, which more closely resemble older individuals. Additionally, the study focused on a specific strain of SARS-CoV-2, and comparative studies are necessary to evaluate the variations in osteochondral damage among different viral variants.
 
In conclusion, this study has elucidated the temporal changes in the bone-cartilage functional unit following SARS-CoV-2 infection. The virus induces endothelial dysfunction and oxidative stress, leading to systemic and local activation of endothelin signaling. This signaling pathway allows viral proteins to leak into local joint tissues, triggering subchondral bone loss, cystic formation, chondrocyte senescence, and cartilage damage. Macitentan, with its ability to block endothelin receptors, has shown promise in mitigating these damaging effects. These findings provide a strong foundation for repurposing endothelin receptor antagonists to manage joint damage and arthralgia in long COVID patients.
 
The study findings were published on a preprint server and are current being peer reviewed for publication into the Nature Portfolio journals.
https://www.researchsquare.com/article/rs-3080850/v1
 
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