Understanding Musculoskeletal Disorders as Major Long-Term Effects of COVID-19

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Musculoskeletal disorders have emerged as prominent long-term consequences of COVID-19, known as Post-Acute Sequelae of COVID-19 (PASC). Among these disorders, arthralgia, or joint pain, stands out as one of the most persistent and challenging symptoms experienced by COVID-19 survivors.

Studies have indicated that between 10% and 23% of hospitalized COVID-19 survivors continue to suffer from arthralgia two to three months after SARS-CoV-2 infection.

Disturbingly, if left untreated, approximately 10% of these individuals develop a debilitating long COVID pain syndrome that can persist for up to a year post-infection.

While joint pain and arthritis have been associated with viral infections in general, emerging evidence suggests a direct link between SARS-CoV-2 infection and joint damage. The exact molecular mechanisms underlying this connection remain elusive, but it is believed that SARS-CoV-2 may trigger hyperinflammation or autoimmune responses, leading to joint damage. One potential mechanism involves the endothelin system, specifically the elevation of endothelin-1 (ET-1) levels, which has been associated with joint damage and pain in both humans and animals.

Research Objectives

In this study, we aimed to investigate the temporal changes in joint pathology following SARS-CoV-2 infection using a well-established golden Syrian hamster model. Our objectives were to characterize the osteochondral damage caused by SARS-CoV-2 infection, examine the activation of endothelin signaling pathways, and evaluate the therapeutic potential of an FDA-approved endothelin receptor blocker, macitentan, in mitigating joint damage.

Methods and Findings

Using the golden Syrian hamster model, we successfully replicated the pathological manifestations of acute SARS-CoV-2 infection. We observed osteochondral damage during the acute phase of infection, accompanied by the activation of endothelin signaling pathways. Notably, the presence of viral spike and nucleocapsid proteins was detected in the subchondral bone marrow cavity of infected hamsters, indicating a possible direct viral insult to the joints.

Furthermore, elevated levels of plasma and endothelial ET-1 were observed in response to SARS-CoV-2 exposure, suggesting a synergistic effect between viral insult and hyperinflammation in driving osteochondral damage.

Based on our findings, we propose that SARS-CoV-2-induced joint damage involves a combination of direct viral insult, hyperinflammation, and the dysregulation of the endothelin system. In addition to the known proinflammatory cytokines implicated in bone loss, such as TNF-alpha and IL-1beta, we identified ET-1 as a potential cytokine contributing to osteoclastogenesis and subsequent bone resorption at the osteochondral junction. Moreover, we found evidence of viral spike-induced senescence in chondrocytes, further highlighting the role of viral insult in joint pathology.

Therapeutic Intervention

To explore potential treatment options, we repurposed macitentan, an FDA-approved drug that blocks both endothelin type A and B receptors, for the treatment of SARS-CoV-2-induced joint damage. Our results demonstrated that timely intervention with macitentan, even during the sub-acute phase of infection, effectively restored the structural integrity of subchondral bone and alleviated joint damage in the hamster model. Macitentan’s therapeutic effects may be attributed to its anti-inflammatory properties, as well as its potential antiviral activity, which has been observed in other viral infections.

Implications and Future Directions

This study provides valuable insights into the pathogenesis of SARS-CoV-2-induced musculoskeletal disorders, specifically osteochondral damage and arthralgia. Our findings highlight the need for early screening of COVID-19 survivors with sustained joint pain to identify structural damage and facilitate timely intervention. Additionally, we underscore the importance of raising public awareness regarding these debilitating long-term skeletal complications associated with post-COVID-19 recovery.

Further investigations are warranted to address the limitations of this study. Specifically, exploring osteochondral damage in aged hamsters to mimic the demographics of human populations and comparing the severity of damage among different SARS-CoV-2 variants will provide a more comprehensive understanding of the disease.

Conclusion

In conclusion, our study elucidates the temporal changes in the bone-cartilage functional unit following SARS-CoV-2 infection in a hamster model. We propose that SARS-CoV-2-induced joint damage involves cellular oxidative stress, endothelial dysfunction, and the activation of endothelin signaling pathways.

The dysregulation of ET-1 contributes to vascular permeability, viral protein leakage into joint tissues, osteoclastogenesis, chondrocyte senescence, and cartilage damage. Importantly, our study highlights the therapeutic potential of endothelin receptor antagonists, such as macitentan, in mitigating SARS-CoV-2-induced joint damage and arthralgia.

These findings provide a scientific foundation for repurposing endothelin receptor antagonists for the management of long COVID-related joint damage and underscore the urgency of prompt intervention and public awareness regarding this debilitating complication. Further research is needed to fully elucidate the underlying mechanisms and validate the therapeutic potential of endothelin receptor antagonists in the context of COVID-19.


Musculoskeletal disorders (MSDs) are a group of conditions that affect the bones, muscles, tendons, ligaments and nerves, causing pain, inflammation, stiffness and disability. MSDs are very common and can affect people of all ages and backgrounds. According to the World Health Organization, MSDs are the second largest contributor to disability worldwide, affecting more than 1.7 billion people.

MSDs can have various causes, such as injury, overuse, aging, infection, autoimmune diseases or genetic factors. Some of the most prevalent MSDs include osteoarthritis, rheumatoid arthritis, low back pain, neck pain, fibromyalgia, gout and osteoporosis. MSDs can impair the quality of life and productivity of affected individuals, as well as increase the burden on health care systems and society.

The management of MSDs is challenging and often requires a multidisciplinary approach that involves pharmacological and non-pharmacological interventions. The pharmacological treatment of MSDs usually includes analgesics, anti-inflammatory drugs, muscle relaxants, corticosteroids and disease-modifying antirheumatic drugs (DMARDs).

However, these drugs may have limited efficacy or cause serious adverse effects, such as gastrointestinal bleeding, renal impairment, cardiovascular events or infections. Therefore, there is a need for new and safer drugs that can effectively treat MSDs and improve the outcomes of patients.

Macitentan is a novel drug that belongs to the class of endothelin receptor antagonists (ERAs). Endothelin is a potent vasoconstrictor and pro-inflammatory peptide that is involved in various pathological processes, such as hypertension, pulmonary arterial hypertension (PAH), fibrosis and inflammation. Endothelin exerts its effects by binding to two receptor subtypes: ETA and ETB. Macitentan is a dual ERA that blocks both ETA and ETB receptors with high affinity and selectivity. Macitentan was initially developed and approved for the treatment of PAH, a rare and life-threatening condition characterized by increased blood pressure in the pulmonary arteries. Macitentan has been shown to reduce the risk of disease progression and hospitalization in patients with PAH by improving hemodynamics, exercise capacity and symptoms.

However, macitentan may also have potential benefits for the treatment of MSDs. Several studies have suggested that endothelin plays a role in the pathogenesis of MSDs by inducing inflammation, pain, tissue damage and remodeling in the affected joints and muscles. Therefore, blocking endothelin receptors with macitentan may reduce the inflammatory response and protect the musculoskeletal tissues from further deterioration. Moreover, macitentan may also have analgesic effects by modulating the nociceptive pathways that mediate pain perception.

The evidence for the efficacy and safety of macitentan in MSDs is still limited and mostly based on preclinical studies or small clinical trials. However, some promising results have been reported in animal models or human subjects with osteoarthritis, rheumatoid arthritis or fibromyalgia. For instance, macitentan has been shown to reduce joint inflammation, cartilage degradation and bone erosion in rats with collagen-induced arthritis or monosodium iodoacetate-induced osteoarthritis. Macitentan has also been shown to improve pain scores, physical function and quality of life in patients with knee osteoarthritis or fibromyalgia in randomized controlled trials.

Macitentan appears to be well tolerated in patients with MSDs, with no major safety concerns reported so far. The most common adverse events associated with macitentan are headache, nasopharyngitis, anemia and edema. Macitentan may also cause liver enzyme elevations or decrease hemoglobin levels in some patients, which require regular monitoring. Macitentan is contraindicated in pregnancy due to its teratogenic effects and can only be prescribed to women of childbearing potential under a risk evaluation and mitigation strategy (REMS) program that ensures effective contraception use.


reference link: https://www.researchsquare.com/article/rs-3080850/v1

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