Using a novel systems biology approach, scientists at the University of California San Diego School of Medicine have further analyzed the cellular players and roles involved in rheumatoid arthritis (RA), a complex disease that affects more than ‘one million Americans in ways that have challenged the development of uniform treatments.
The findings, published in the October 20, 2022 issue of Nature Communications, show that the same molecules involved in RA can have opposite functions in cells obtained from different patients; and help explain why current targeted therapies evoke different responses in patients with the same diagnosis and similar symptoms.
Arthritis encompasses more than 100 conditions that affect the joints, the tissues around the joint, and other connective tissues. It is estimated that more than 58 million adults in the United States (one in five) have been diagnosed with the disease.
Osteoarthritis is the most common form, involving degeneration of the joints, often in the hands, hips and knees. RA is less common, but still affects more than two million Americans, mostly women. It is a systemic autoimmune disease characterized by painful or long-lasting or chronic tissue inflammation in the affected joints. It can also cause problems in other organs, such as the lungs, heart and eyes.
The causes and risk factors of RA are countless and not well understood. They range from age, sex and lifestyle (such as smoking) to obesity and inherited traits. There is no cure for RA, but there is a wide range of targeted treatments that can help slow the progression of the disease, prevent joint deformity, and reduce pain and disability.
Although this RA emerges with a similar clinical appearance between patients, the response to any individual treatment is unpredictable and requires trial and error. This process is repeated until a drug is identified that decreases disease activity for that particular patient.”
Gary Firestein, MD, co-corresponding author, distinguished professor of medicine and director of the Altman Institute for Clinical and Translational Research, UC San Diego School of Medicine
“Many patients have improved outcomes, but a significant percentage do not. They have persistent inflammation. These variable responses to therapy indicate that the same disease may have multiple mechanisms.”
This diversity or heterogeneity of the disease with different cell types in individual RA patients has driven efforts to find personalized mechanisms that help better understand the nature of RA and reliably prescribe early and effective treatment. In the new study, the UC San Diego team focused on fibroblast-like synoviocytes (FLS), a type of specialized cell found inside joint synovium; a soft connective tissue that lubricates the joints and minimizes wear and tear. FLSs play an important role in the joint destruction of RA.
By examining cultured primary FLS, the researchers identified specific transcription factors (proteins that regulate gene transcription or copying) that are involved in individual RA patient cell lines. The analysis allowed the scientists to stratify these cell lines into at least two subtypes with different predicted activated pathways that could contribute to inflammation.
“Essentially, we biologically validated these predictions for major subtype-specific transcription factors,” said corresponding author Wei Wang, PhD, a professor in the departments of Chemistry, Biochemistry, and Cellular and Molecular Medicine at the UC San Diego School of Medicine. of Medicine. “This study is the first to characterize groups of RA patient cell lines with distinctive transcription factor biology by integrating transcriptomic and epigenomic data.”
Systems biology is a computational approach that studies the interactions and behavior of all the components of a biological entity, based on the understanding that the whole is greater than the sum of its parts. By taking this approach, the authors wrote, the findings could help pave the way to a better understanding of the heterogeneity of RA while providing a better focus on existing and future therapies tailored to individual patients.
Source:
University of California San Diego
Journal reference:
Ainsworth, RI, et al. (2022) Systems and biology analysis of fibroblast-like synoviocytes from rheumatoid arthritis implicates cell line-specific transcription factor function. Communications of nature. doi.org/10.1038/s41467-022-33785-w.