The study finds an inflammatory mechanism that is responsible for bone erosion in rheumatoid arthritis

Publicado em 18 março 2021

In a study aimed at investigating the mechanism responsible for exacerbating rheumatoid arthritis in smokers, researchers at the Center for Research on Inflammatory Diseases (CRID), affiliated with the University of São Paulo (USP) in Brazil, discovered a new pathway in the inflammatory process associated with bone damage caused by rheumatoid arthritis. The discovery opens up opportunities for new therapeutic interventions to mitigate the effects of the disease, for which there is no specific treatment at present.

An article about the study is published in Proceedings of the National Academy of Sciences (PNAS). The researchers identified the effect of a molecular mechanism involved in the inflammatory process: the release of T lymphocytes by extracellular vesicles loaded with genetic material (microRNA). The blisters reach cells in bone tissue, which increases the formation of osteoclasts, cells that break down the bone matrix in the joints (a critical function in bone maintenance, repair and reconstruction).

“The study aimed to broaden our understanding of how cigarette smoke exacerbates the inflammatory process in rheumatoid arthritis. We discovered a pathway associated with bone damage. This is an important result because pain and inflammation have been treated with medication, but bone damage is a debilitating complication. of this disease is practically irreversible, “he said Fernando de Queiroz Cunha, Principal Investigator for CRID, one of the research, innovation and dissemination centers (RIDC) is supported by FAPESP.

Rheumatoid arthritis is an autoimmune disease in which the immune system, for unknown reasons, suspects parts of the patient’s body of an invading pathogen and attacks them. The inflammation triggered by the immune system’s overreaction is known to involve Th17 cells, a T cell subtype, and to create cascade effects such as the release of cytokines (signal proteins), including IL-17, as well as other molecules involved in disease progression.

Smoking is known to be an aggravating factor for rheumatoid arthritis. Previous research from the same CRID group showed that cigarette smoke exacerbates the inflammatory process in arthritis mainly by activating the aryl hydrocarbon receptor (AhR) on Th17 cells.

“AhR is an intracellular sensor that identifies contaminants involved in the inflammatory process. When AhR is activated on T cells by certain ligands, they differ even more from Th17. The increase in Th17 cells exacerbates the inflammatory process. Although smoking does not cause “Rheumatoid arthritis, it makes the disease worse,” he said Paula Donera, a CRID researcher whose postdoctoral research was supported by FAPESP.

Donate explained that AhR acts primarily as a transcription factor. “If this receptor is activated by an external agent such as cigarette smoke, it enters the cell nucleus along with other proteins and promotes the transcription of various genes, including microRNAs, which are small regulatory RNAs inside the cell,” she said.

Extracellular component

In the study, the researchers wanted to find out which microRNAs in Th17 cells were expressed more due to AhR activation. Their analysis pointed to miR-132. They analyzed the whole set of microRNAs expressed by Th17 cells and correlated the results with data from a laboratory experiment with mice and human patient samples.

“To our surprise, however, when we treated T cells with antagonists of the microRNAs, they continued to differentiate normally into Th17 cells, releasing the cytokines that are characteristic of the inflammatory process in rheumatoid arthritis. If it had not no effect on the intracellular process it was a sign that miR-132 could be released into the extracellular medium, says Donate.

When the researchers isolated extracellular vesicles released by Th17 and studied them in vitro, they found that the large amounts of miR-132 packaged in extracellular vesicles acted as inflammatory mediators, inducing differentiation of osteoclasts via inhibition of the enzyme cyclooxygenase 2 (COX-2).

“Extracellular vesicles are a key cellular communication mechanism. They are released by virtually all cell types and are found in all types of body fluid. In the case of Th17 cells, the vesicles released in joints can transport microRNA to bone tissue and increase the amount of osteoclasts and bone erosion. a previously unknown mechanism that we managed to shed light on and which in the future may be a basis for new therapies for joint damage, says Donate.


About the São Paulo Research Foundation (FAPESP)

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