Osteopontin Protein May Be Cause of Lung Scarring in Scleroderma

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by Joana Carvalho |

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scleroderma and PAH

Osteopontin, a protein known to play a role in tissue regeneration, immune system regulation, and bone remodeling, may be driving scarring of lung tissue in people with scleroderma associated with interstitial lung disease (SSc-ILD), a study suggests.

High levels of osteopontin — produced by a subtype of immune cells that are overactive in scleroderma — are linked with disease progression and poorer lung function in these patients.

Researchers also found that tocilizumab, an immunosuppressant sold as Actemra by Genentech in the U.S. and used to treat rheumatoid arthritis and other autoimmune diseases, can lower osteopontin levels and possibly counteract the protein’s harmful effects.

“Osteopontin has potential to be a promising biomarker and potential target for future therapies for those with SSc-ILD,” Dinesh Khanna, MD, director of Michigan Medicine’s Scleroderma Program, and author of the two studies on osteopontin and tocilizumab, said in a university press release.

“If you asked our team what one disease we wish we had a treatment for, we’d say scleroderma,” Khanna added. “We’ve accepted the challenge of trying to help patients the best we can, by continuing a search for a treatment or cure.”

Scleroderma, also known as systemic sclerosis (SSc), causes inflammation and tissue scarring (fibrosis) in the skin and internal organs that can include the heart, kidneys, and lungs.

Over time, lung tissue scarring can compromise lung function and lead to ILD, a common complication of scleroderma.

Even though progressive lung fibrosis is one of the major causes of disease progression in these people, its underlying cellular and molecular mechanisms are still poorly understood. In an attempt to identify some of these mechanisms, and possibly disease biomarkers that could be valuable therapeutic targets, Khanna collaborated with Thirumalai Ramalingam, PhD, an expert in fibrosis biomarkers at Genentech (part of the Roche group).

They set out to explore the possible links among self-reactive antibodies associated with autoimmunity, immune cell activation, and progressive lung fibrosis in people with SSc associated with ILD (SSc-ILD).

After analyzing more than 29,000 cells isolated from lung tissue of three people with SSc-ILD, they identified a protein, called osteopontin, that seemed to act as a driver of lung fibrosis.

In the study “Osteopontin Links Myeloid Activation and Disease Progression in Systemic Sclerosis,” published in the journal Cell Reports Medicine, Khanna, Ramalingam and colleagues demonstrated that osteopontin is produced in high amounts by a subset of immune cells, called macrophages, that are overactive in these patients.

“When the macrophage is activated by immune complexes, we discovered that it secretes an abundance of a protein called osteopontin — previously implicated in fibrosis,” Ramalingam said.

They also found that this process seemed to be enhanced by the presence of interleukin-6 (IL-6), a pro-inflammatory molecule, and monocyte colony stimulating factor, a growth factor that controls the expansion and activation of certain immune cells.

Subsequent analyses linked high blood levels of osteopontin in the patients with disease worsening and lung function deterioration.

Treatment with tocilizumab, which works by blocking the activity of the IL-6 receptor, successfully lowered blood levels of osteopontin in people who took part in the FocuSSced Phase 3 trial (NCT02453256). These findings not only confirmed the involvement of IL-6 in the process leading up to excessive osteopontin production, but also suggested tocilizumab as an effective treatment to counter the protein’s effects.

Tocilizumab’s potential to treat people with SSc-ILD was assessed in a second study by Khanna, which reported the findings of FocuSSced. This Roche-sponsored trial was designed to evaluate the medication’s safety and efficacy at reducing skin thickness, improving lung function, and other physician and patient-reported outcomes.

FocuSSced enrolled a total of 212 adults with scleroderma, who were randomly assigned to either 162 mg of tocilizumab or a placebo, delivered once weekly as an under-the-skin injection for 48 weeks (nearly one year).

Data from the trial, recently published in journal The Lancet Respiratory Medicine, showed that even though tocilizumab was not superior to the placebo at reducing skin thickness, its use improved patients’ lung function over 48 weeks. This was reflected by a significant improvement in forced vital capacity — a measure of the total amount of air a person is able to exhale after a deep breath — in patients treated with tocilizumab compared with those given a placebo.

Based on these findings, the team said that tocilizumab might help preserve lung function in people with early SSc-ILD.

No differences, however, were found between both treatment or placebo on physician- or patient-reported outcomes.

Infections were the most common adverse event reported in patients treated with tocilizumab (52%) and in those given a placebo (50%). The incidence of serious adverse events was also similar in both groups (13% in the tocilizumab group and 17% in the placebo group); most commonly, these events were infections and cardiac complications.

“The potential effect of tocilizumab in preserving lung function in patients with early SSc-ILD … has important therapeutic implications, including potential to prevent progression of a major disease complication,” the scientists wrote.