Distinct Fibroblast Subsets Drive Inflammation and Damage in Arthritis

By Nicole Zhao ‘20 

Figure 1. Dysregulation of fibroblasts often results in pathological diseases. 

Arthritis is an inflammation of one or more joints with symptoms such as joint pain and stiffness (1). One common type of arthritis is rheumatoid arthritis, an inflammatory disease in which the immune system targets the synovial membrane of the joints and causes joint damage (1). The synovial membrane normally protects and lubricates the joints. Previous studies have found that the dysregulation of fibroblasts, active cells that reside in tissues, is responsible for a multitude of diseases (2). Fibroblasts are normally responsible for regulating extracellular matrices, interstitial fluid volume and pressure, and wound healing (2). Moreover, it has been established that distinct fibroblast phenotypes are responsible for different diseases at different sites. However, it is unclear whether fibroblast subclasses exist and are responsible for inflammation and damage in immune mediated inflammatory diseases such as rheumatoid arthritis. 

In a study conducted by researchers at the Queen Elizabeth Hospital in the United Kingdom, it was found that the expression of fibroblast activation protein alpha (FAP- α) was significantly higher in the synovial tissue of patients with rheumatoid arthritis compared to patients in which the disease was resolved (3). FAP- α is an enzyme on the cell membrane normally associated with immune regulation, signal transduction, and apoptosis. This finding suggests that FAP- α expression may be associated with a pathogenic fibroblast phenotype. To test this hypothesis, researchers mapped FAP- α expression in FAP- α+ synovial fibroblasts in mouse models over the course of arthritis. It was found that FAP- α expression increased during disease progression and correlated with the severity of ankle joint swelling (3). 

To determine the functional role of FAP- α+ fibroblasts, researchers removed them in mice with rheumatoid arthritis. It was found that this deletion led to a significant reduction in inflammation and bone erosion regardless of the stage of the disease (3). Single-cell transcriptional analysis further identified two distinct fibroblast subsets that express FAP- α. One population is the FAPα+THY1+ fibroblasts located in the synovial sub-lining that respond to the immune system and the other is the FAPα+THY1− destructive fibroblasts restricted to the synovial lining layer (3). It was found the FAPα+THY1− fibroblasts mediate bone and cartilage damage while FAPα+THY1+ fibroblasts caused more severe inflammation (3). 

These findings are important in that two subsets of pathological fibroblasts were identified and specific to their location, further adding to the classification of fibroblasts that make up our tissues. The identification of increased FAP- α expression in patients with rheumatoid arthritis suggests another strategy to combat the disease. 


  1. Arthritis. Mayo Clinic, (2018). 
  2. J. Mcnulty. Fibroblasts and myofibroblasts: their source, function and role in disease. The International Journal of Biochemistry & Cell Biology 39, 666-671 (2007). doi: 10.1016/j.biocel.2006.11.005. 
  3. A. Croft, et. al., Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature (2019). doi: 10.1038/s41586-019-1263-7. 
  4. Image retrieved from: http://sjabioscience.com/page/2/

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