What Scientists Are Learning About Fibroblasts in TED Progression

Thyroid eye disease (TED), or Graves’ orbitopathy, is a complex autoimmune condition that causes inflammation and tissue remodeling behind and around the eyes (1,2). It is a leading cause of cosmetic and functional eye problems in adults and can exist in conjunction with or without overt manifestations of thyroid disorders like Graves’ disease. In TED, the immune system begins to attack the tissues within the orbit (eye sockets), leading to inflammation and the associated symptoms. In this context, it is important to understand the role of the central orbital fibroblasts (connective tissue cells in the orbit) in the disease’s progression, symptom severity, and the development of novel TED treatment strategies (3). The behavior of these orbital fibroblasts and their interactions with normal tissue, particularly their contribution to fibrosis (scarring) and tissue expansion, is a major cause of many of the most troublesome symptoms of TED (4). Understanding these insights is crucial to managing and treating TED at a cellular and molecular level.

What are Orbital Fibroblasts?

Orbital fibroblasts are specialized connective tissue cells found within the eye socket. Unlike fibroblasts in other parts of the body, these cells characteristically express higher levels of certain receptors, such as the thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1R) 5. Graves’ disease is characterized by autoantibodies that target the TSH receptor (TSHR). When these antibodies bind to TSHR on orbital fibroblasts, they stimulate and activate these cells. Activated fibroblasts then secrete large amounts of proinflammatory cytokines, extracellular matrix proteins, and hydrophilic (water-loving) molecules like hyaluronan that draw excessive fluid into the orbit. This activation contributes directly to the thyroid eye disease symptoms that TED patients experience, such as proptosis (eye bulging), extraocular muscle swelling, eyelid retraction, restricted eye movement, diplopia (double vision), corneal exposure, irritation, and even optic nerve compression in severe cases. This inflammation is predominant in the early stages of the disease, and in later stages it evolves towards tissue remodeling and fibrosis, where the TED fibroblasts and their derivatives produce dense extracellular matrix (ECM) that stiffens the orbital tissues and can make changes permanent.

Fibroblasts and Fibrosis

Recent cutting-edge approaches to examine fibroblast behavior under conditions that more closely mimic the living orbital environment have helped reveal the roles of orbital fibroblasts and fibrosis in TED development 6. Rather than traditional flat (two-dimensional) laboratory cultures, TED orbital fibroblasts, when grown as three-dimensional (3D) spheroids (tiny ball-like clusters that allow cells to interact with each other and their surroundings), showed increased contractility and tissue remodeling. These 3D spheroids formed dense, contractile structures with a fibrous ring at the edges, which is a hallmark of activated fibrosis-prone cells. These 3D models exhibited greater contractile strength and denser extracellular matrix (ECM) deposition than fibroblasts from people without TED. The fibroblast’s ability to contract and alter the surrounding ECM promotes tissue stiffening and remodeling in advanced TED, contributing to symptoms such as eye bulging and limited motility. These cultures also had higher fibrosis marker expression, with markers of fibrosis such as alpha-smooth muscle actin (α-SMA), type I collagen (COL1A1), and fibronectin (FN1) significantly elevated in the TED orbital fibroblasts cultured in the 3D model compared with cells from unaffected controls. This indicates that these cells are not just inflamed but actively engaged in the scarring process. This closer mimicry of real orbital tissue conditions in TED also showed that the gene expression patterns in the 3D model fibroblasts (TED-3D) more closely resembled those of actual orbital tissue than those in traditional 2D cultures.

Breaking Down the Orbital Fibroblast Subtypes

Orbital fibroblasts in TED are not a uniform cell type, and they can differentiate into adipocytes (fat-producing cells), which contribute to the expansion of orbital fat and myofibroblasts (fibrosis-producing cells) that are responsible for stiffness and scarring 7. The balance between these two pathways may help explain why some people develop more fat expansion (leading to proptosis) while others develop significant fibrosis and eye motility issues. Additionally, proinflammatory cytokines like IL-6, IL-16, and CCL5(receptor signaling through TSHR and IGF-1R) influence which pathway or cell type predominates the other.

Orbital Fibroblasts and Autoimmunity

Orbital fibroblasts interact closely with the immune system. Activated T-cells and B-cells produce cytokines that stimulate fibroblasts, which in turn secrete more inflammatory mediators, creating a self-amplifying inflammatory and autoimmune loop. This helps explain the persistence of TED post initiation, fibroblast activation, which can sustain inflammation and tissue remodeling even when thyroid hormone levels become under control. Also, subpopulations of fibroblasts such as those expressing the CD34 marker may have distinct roles in disease progression, with recent studies suggesting that CD34+ orbital fibroblasts contribute importantly to inflammatory signaling and may be involved in disease severity 8.

Importance in Treatment

Historically, most TED therapies (like corticosteroids) have focused on reducing inflammation. While that remains important, particularly for acute, active disease, acknowledging and understanding fibroblast biology opens the door to treatments that specifically target fibrosis and tissue remodeling rather than only decreasing inflammation. Such therapies could prevent or reverse fibroblast differentiation into myofibroblasts, potentially reducing permanent tissue changes that lead to chronic motility problems and disfigurement. Targeted therapies can also constrain receptor-mediated activation with drugs like teprotumumab (Tepezza), which block the IGF-1R signaling complex on orbital fibroblasts and were among the first to target fibroblast activation directly and have shown dramatic reductions in proptosis and disease activity in clinical trials. These advances align with what scientists are learning about how fibroblasts drive disease.

Plus, by understanding the genes and pathways that control collagen and fibronectin production, new therapies may modulate extracellular matrix deposition (ECM), the process that is key to fibrosis and tissue stiffness. So, as we study more about fibroblast subtypes and their signaling pathways, future therapies may be personalized based on whether a TED patient’s disease is driven more by adipogenesis, fibrosis, or immune signaling.

In all, these advances promise more effective, targeted thyroid eye disease treatment, thereby moving beyond broad immunosuppression toward precise modulation of the cells that make TED so challenging to combat.

New Insights Into TED Fibroblasts Are Leading to Better, More Targeted Care

Orbital fibroblasts, once considered passive structural cells, are now recognized as active drivers of activation and TED progression. They respond to autoimmune signals, produce proinflammatory mediators, differentiate into cells that expand orbital fat, and lay down fibrotic collagen that stiffens orbital tissues. Hence, understanding TED fibroblast behavior is not just a scientific curiosity but a pathway to better, more effective thyroid eye disease treatment. If you are interested in learning more about newer targeted treatment options for TED, do not hesitate to schedule an appointment with Dr. Raymond Douglas.

References

1. Shah, S. S. & Patel, B. C. in StatPearls     (2025).
2. Edmunds, M. R. & Boelaert, K. Knowledge of Thyroid Eye Disease in Graves’ Disease Patients With and Without Orbitopathy. Thyroid 29, 557-562 (2019). https://doi.org/10.1089/thy.2018.0665
3. Dik, W. A., Virakul, S. & van Steensel, L. Current perspectives on the role of orbital fibroblasts in the pathogenesis of Graves’ ophthalmopathy. Exp Eye Res 142, 83-91 (2016). https://doi.org/10.1016/j.exer.2015.02.007
4. Moledina, M., Damato, E. M. & Lee, V. The changing landscape of thyroid eye disease: current clinical advances and future outlook. Eye (Lond) 38, 1425-1437 (2024). https://doi.org/10.1038/s41433-024-02967-9
5. Gupta, V.et al. Thinking inside the box: Current insights into targeting orbital tissue remodeling and inflammation in thyroid eye disease. Surv Ophthalmol 67, 858-874 (2022). https://doi.org/10.1016/j.survophthal.2021.08.010
6. Bao, X.et al. Three-Dimensional Culture of Orbital Fibroblasts From Thyroid Eye Disease Induce In Vivo-Like Tissue Remodeling and Fibrosis. Invest Ophthalmol Vis Sci 66, 67 (2025). https://doi.org/10.1167/iovs.66.6.67
7. Kuriyan, A. E., Woeller, C. F., O’Loughlin, C. W., Phipps, R. P. & Feldon, S. E. Orbital fibroblasts from thyroid eye disease patients differ in proliferative and adipogenic responses depending on disease subtype. Invest Ophthalmol Vis Sci 54, 7370-7377 (2013). https://doi.org/10.1167/iovs.13-12741
8. Yu, B.et al. CD34+ Orbital Fibroblasts Contribute to the Pathogenesis of Thyroid Eye Disease via miR-182-5p. J Clin Endocrinol Metab 110, 2631-2644 (2025). https://doi.org/10.1210/clinem/dgae876