Rheumatology Research Group

The smooth functioning of synovial joints, such as the knees and hips, is essential for maintaining mobility and quality of life as we age. In the Western World, arthritis is a leading cause of disability and its total costs (both direct and indirect) in the UK have been estimated to exceed £30 billion annually. Its high prevalence and heavy impact on work capacity make arthritis a major social issue.  

Osteoarthritis is the most common joint disease, affecting around 10 million people in the UK. It involves progressive joint tissue damage with breakdown of articular cartilage, and the disease process is often triggered by injury or trauma and exacerbated by obesity. Current treatments are limited to symptom relief with pain-killers and to joint replacement in end-stage disease. There is therefore an unmet need for new treatments that can prevent disease development or progression. 

Rheumatoid arthritis is the most common chronic inflammatory joint disease, affecting approximately 700,000 people in the UK. Despite significant therapeutic advances with immunosuppressive disease-modifying anti-rheumatic drugs, inflammatory joint diseases can still cause joint damage, resulting in deformities and disability. 

Our work encompasses several interconnected research topics: 

1) We investigate the endogenous stem and progenitor cells that reside in the joint tissues and how they replenish mature stromal cells that are lost due to normal tissue turnover or injury. We also investigate why these cells fail to repair joints and instead contribute to joint damage in arthritis.  

2) We study the biology of fibroblast-like synoviocytes (FLS), a specialised cell type in the synovial lining crucial for maintaining healthy joint tissues. We study how these cells are molecularly controlled and how they become dysfunctional in arthritis. 

3) We determine the mechanisms of cartilage repair and evaluate therapeutic approaches that promote endogenous repair processes for the treatment of cartilage lesions or early-stage osteoarthritis.  

4) We seek to develop methods for early detection and diagnosis, patient stratification, and targeted therapy for arthritis. 

Stem and progenitor cells (SPCs) have been identified within various joint-associated tissues. Among the most highly investigated are SPC populations residing within bone marrow, which include cells around sinusoids and arterioles, and at endosteal surfaces. SPCs are also present in the superficial zone of articular cartilage and in the membranes that surround the joint and its related structures, including the synovium and periosteum. In the synovium, SPCs are present among the Prg4-expressing cells in the lining and among the fibroblasts in the vascularized sublining. FLS, fibroblast-like synoviocyte; MLS, macrophage-like synoviocyte. First published in Roelofs et al., Nature Reviews Rheumatology 2025, 21(4):211-220, by Springer Nature. 

Our genetic cell-lineage tracing studies have revealed that the precursors of the SPCs that specialise in maintaining and repairing joint tissues in adult life are seeded in the joint tissues during their formation in the womb. Specifically, they originate from the cells of the joint interzone that orchestrate the process of synovial joint formation in the embryo (Roelofs, Zupan et al., Nat Commun 2017).   

This discovery provided a rationale for the targeting of synovial SPCs for regenerative therapies aimed at restoring joint tissues. In collaboration with other research groups, we have demonstrated that the cartilage reparative capacity of SPCs can be enhanced through the local administration of pro-chondrogenic factors or cells (Eldridge et al., Sci Transl Med 2020; Perry et al., Cells 2021). 

Our work has further revealed the crucial roles of these ontogenetically defined SPCs in arthritis. In osteoarthritis, these cells are key drivers of the tissue remodelling that leads to the formation of osteophytes, bony growths at the edges of the joint. Through extensive genetic cell-lineage tracing studies, we demonstrated that this process is mediated by a cooperation between two populations of SPCs that reside in the membranes that support and enclose the joint tissues, the periosteum and synovial lining (Figure 1) (Roelofs, Kania et al., Ann Rheum Dis 2020).  

Utilising single-cell RNA-sequencing, we confirmed the existence of a population of synovial lining SPCs that are distinct from the fibroblast-like synoviocytes (FLS) (Figure 1). In addition to being chondrogenic, we showed that these SPCs proliferate and supply new FLS after acute joint injury (Collins, Roelofs et al., Ann Rheum Dis 2023).  

We also demonstrated that SPCs originating from the joint interzone give rise to intra-articular adipose tissue in the knee shortly after birth. Blocking adipogenesis in these SPCs resulted in a reduced, inflamed adipose tissue without affecting cartilage integrity or osteoarthritis progression following mechanical damage. However, cartilage damage was exacerbated in obesity due to a high-fat diet, highlighting the role of intra-articular adipose tissue in lipid homeostasis and illustrating the impact of diet on joint health (McClure et al., Osteoarthritis Cartilage 2024). 

In inflammatory arthritis, we demonstrated that the joint-interzone-derived cell lineage undergoes extensive proliferation and expansion, and gives rise to invasive fibroblasts that mediate joint destruction. We identified a critical role for the transcriptional co-factor Yap, which operates downstream of IL-6, a key inflammatory cytokine in rheumatoid arthritis. Upon IL-6 signalling, Yap binds to the transcription factor Snail, driving the pathological transformation of synovial fibroblasts (Symons, Colella et al., Ann Rheum Dis 2022). 

In a study led by Prof Gordon Brown and his team (Exeter University), we have identified an autoregulatory loop that controls neutrophil activation and is dysregulated in rheumatoid arthritis. Myeloid inhibitory C-type lectin-like (MICL) recognises DNA in neutrophil extracellular traps (NETs) and negatively regulates neutrophil activation. In diseases like rheumatoid arthritis, lupus and severe COVID-19, autoantibodies inhibit MICL, leading to dysregulation of NET formation and more severe pathology (Malamud et al., Nature 2024).