Fibroblast Growth Factor 18 (FGF18): The Multifaceted Role from Developmental Regulation to a Therapeutic Star

1.        What is Fibroblast Growth Factor 18, and what is its position in the FGF family?

Fibroblast Growth Factor 18 (FGF18) is a member of the Fibroblast Growth Factor (FGF) family, which consists of 22 structurally related signaling proteins that play key roles in regulating critical biological processes such as cell proliferation, differentiation, migration, and survival in mammals. FGF18 was first discovered and cloned in 1998, and its gene is located on human chromosome 5q35.1. Phylogenetically, FGF18, along with FGF8 and FGF17, belongs to the FGF8 subfamily (also known as the paracrine FGF subfamily). These proteins share high amino acid sequence homology but perform unique and irreplaceable functions in vivo. Unlike FGF19, FGF21, and FGF23, which primarily act through endocrine mechanisms to target distant organs, FGF18 is a typical paracrine signaling molecule. This means it is synthesized and secreted by cells and primarily acts on neighboring cells. Its activity is strictly regulated by binding to heparan sulfate proteoglycans (HSPGs), which is essential for forming a stable ternary complex with its receptors. This binding restricts its range of action, ensuring precise and localized signal transduction. FGF18 specifically binds to and activates Fibroblast Growth Factor Receptors (FGFRs) on the cell membrane, with the highest affinity for the FGFR2c and FGFR3c receptor subtypes. Upon receptor activation, intracellular downstream signaling pathways such as RAS/MAPK, PI3K/AKT, PLCγ, and STAT are initiated, ultimately converting extracellular signals into specific nuclear biological responses. This process enables FGF18 to play a conductor-like role in embryonic development, tissue homeostasis, and repair and regeneration.

2.        What key biological functions does FGF18 play in embryonic development and the adult body?

The expression of FGF18 exhibits significant temporal and spatial specificity, and its functions span multiple stages from embryonic development to adulthood, particularly playing a central role in the development and homeostasis of the skeletal system. During embryonic development, FGF18 is a key regulator of bone formation (osteogenesis). It precisely controls bone growth and patterning by coordinating the proliferation, differentiation, and apoptosis of chondrocytes during endochondral ossification. In the growth plate, FGF18 is primarily produced by surrounding periosteal cells and hypertrophic chondrocytes. By activating FGFR3 on chondrocytes, it strongly inhibits chondrocyte proliferation while promoting their differentiation into the hypertrophic stage. This process ultimately guides vascular invasion and calcification of the cartilage matrix, preparing for the replacement of bone tissue. Gene knockout studies have clearly demonstrated the importance of FGF18: mice deficient in Fgf18 exhibit severe skeletal developmental abnormalities, including significantly shortened long bones, defects in sternal fusion, craniosynostosis, and alveolar hypoplasia. These findings fully confirm the indispensable role of FGF18 in normal skeletal patterning and growth.

Beyond its central role in the skeletal system, FGF18 also plays multiple roles in other tissues and organs. In the central nervous system, FGF18 is expressed in specific regions of the embryonic brain (such as the cortex and hippocampus), where it regulates the survival and differentiation of neural precursor cells, influencing normal brain development and circuit formation. In the lungs, it promotes the proliferation of alveolar epithelial cells and branching morphogenesis, which is crucial for normal lung development. In the adult body, although the expression level of FGF18 decreases, it does not become silent. It continues to be expressed at low levels in tissues such as bones, articular cartilage, the liver, and the brain, participating in the maintenance of tissue homeostasis. Particularly in articular cartilage, FGF18 exhibits a dual function: on one hand, it can exert anabolic effects by promoting the proliferation of chondroprogenitor cells and matrix synthesis; on the other hand, in an inflammatory environment, it may also participate in catabolic processes. Furthermore, increasing evidence suggests that FGF18 is reactivated during injury repair and regeneration processes. For example, in models of fracture healing, liver regeneration after partial hepatectomy, and muscle injury, the expression of FGF18 is significantly upregulated, indicating that it may be an important signaling molecule in the tissue's response to injury and initiation of repair programs.

3.        What role does FGF18 play in the occurrence and development of diseases, and what are the mechanisms?

Dysregulation of FGF18 signaling, whether due to overactivation or functional deficiency, is closely associated with the pathological processes of various human diseases, making it a disease-related molecule of great interest and a potential therapeutic target. In the field of skeletal and joint diseases, abnormal enhancement of the FGF18-FGFR3 signaling axis is a major cause of skeletal developmental disorders such as achondroplasia and thanatophoric dysplasia. These diseases are typically caused by constitutive activating mutations of FGFR3, leading to sustained and intense activation of the FGF18/FGFR3 signaling pathway. This overactivation excessively inhibits the proliferation of growth plate chondrocytes, resulting in severe limb shortening and dwarfism. On the other hand, in osteoarthritis (OA), the progressive degeneration of articular cartilage is a core feature. Although the pathology of OA is complex, the FGF signaling network plays a contradictory role. Some studies have shown that in osteoarthritic joints, the expression patterns of FGF18 and its receptors are altered, and the balance of signaling is disrupted, potentially contributing to the process of cartilage degradation. However, interestingly, exogenous supplementation of recombinant FGF18 protein has been shown to stimulate chondrocyte proliferation and the synthesis of extracellular matrix components (such as proteoglycans and type II collagen), demonstrating strong cartilage-protective potential. This highlights the complex and context-dependent functions of FGF18 signaling in joint health and disease.

Beyond the skeletal system, abnormal expression of FGF18 has also been linked to the occurrence and development of tumors. Multiple studies have found that FGF18 expression levels are significantly higher in various solid tumors, such as hepatocellular carcinoma, colorectal cancer, non-small cell lung cancer, and prostate cancer, compared to adjacent normal tissues. Through its mitogenic, angiogenic, and anti-apoptotic properties, FGF18 provides growth advantages for malignant proliferation and survival of tumor cells in an autocrine or paracrine manner. For example, in hepatocellular carcinoma, highly expressed FGF18 drives tumor cell proliferation and inhibits apoptosis by activating FGFR4 and the downstream ERK signaling pathway, which is associated with poor clinical prognosis. Additionally, FGF18 can stimulate the formation of new blood vessels in the tumor stroma, providing sufficient oxygen and nutrients for rapidly growing tumors. Therefore, targeting the FGF18/FGFR signaling axis has become an emerging direction in cancer therapy. Monoclonal antibodies and small-molecule inhibitors targeting this pathway are currently being evaluated in preclinical and clinical studies to disrupt this critical signaling route that drives tumor growth.
 

4.        What is the current research status and future prospects of FGF18 as a therapeutic drug?

Given the strong potential of FGF18 in promoting tissue repair and regeneration, its development as a therapeutic drug, particularly for treating injuries and degenerative diseases of the musculoskeletal system, has become a hotspot in the biomedical industry. Currently, the most notable progress is focused on its therapeutic application for osteoarthritis. Recombinant human FGF18 (such as Sprifermin) as a locally administered biologic has shown great promise in preclinical models and human clinical trials. In animal models, intra-articular injection of Sprifermin significantly stimulated the regeneration and thickening of articular cartilage, increased the synthesis of cartilage matrix components, and slowed the progression of cartilage defects. Subsequent multiple randomized, double-blind, placebo-controlled Phase II clinical trials showed that, compared to placebo, intra-articular injection of Sprifermin twice a year significantly and sustainably increased the cartilage thickness of the femoral condyle in the knee joint, indicating its potential as a Disease-Modifying Osteoarthritis Drug (DMOAD). Although its effects on pain relief have been inconsistent, its ability to promote cartilage regeneration offers unprecedented hope for fundamentally treating osteoarthritis. Currently, larger-scale Phase III clinical trials are being planned or conducted to further validate its long-term efficacy and safety.

Beyond osteoarthritis, FGF18 has also demonstrated therapeutic value in fracture healing and cartilage repair. Preclinical studies have shown that local application of FGF18 can accelerate the fracture healing process, promote callus formation and bone remodeling, and improve the quality of healed bone. This has important clinical significance for treating delayed union or non-union fractures. In the field of periodontal tissue regeneration, FGF18 has also been explored for promoting the regeneration of alveolar bone and periodontal ligaments. Looking ahead, the therapeutic applications of FGF18 may further expand. Its basic research functions in neuroprotection and liver regeneration suggest that it may be used in the future to treat nervous system injuries, neurodegenerative diseases, and promote functional recovery after liver surgery. However, successfully translating FGF18 into a widely used drug still faces many challenges. Its inherent heparin-binding properties may cause retention at the injection site and potentially lead to off-target effects. Precisely controlling its dosage, frequency, and delivery methods is crucial to maximize its anabolic benefits while minimizing the theoretical risk of promoting abnormal hyperplasia or tumor growth. Additionally, developing more stable and targeted FGF18 variants or analogs, as well as combining them with advanced biomaterial scaffolds for localized sustained release, will be important directions for future research.
 

Summary and Outlook: What are the future research directions for FGF18?

Fibroblast Growth Factor 18 (FGF18) is a multifunctional signaling protein whose biological functions extend far beyond what its name implies. From directing the precise construction of the embryonic skeleton to maintaining tissue homeostasis in adults and responding to injury to initiate repair programs, FGF18 plays a role throughout life. It is both a key guardian of health in the correct spatiotemporal context and a driver of various diseases (from skeletal deformities to cancer) when its signaling pathway is dysregulated. This functional duality presents both challenges and great opportunities: on one hand, we need to gain a deeper understanding of its complex and context-dependent signaling regulatory mechanisms; on the other hand, it provides us with a powerful molecular tool for developing innovative therapies for osteoarthritis, fracture non-union, and even certain cancers. Future research will focus more on deciphering the precise mechanisms of FGF18 in different tissue microenvironments, developing a new generation of safer and more efficient therapeutic strategies (such as tissue-targeted delivery, functionally optimized protein variants, and combination with biomaterials), and actively exploring its potential applications in new fields such as neural regeneration and cardiovascular diseases. With the continuous advancement of basic science and translational research, FGF18 is expected to transform from an important basic biological molecule into a revolutionary therapeutic drug that truly benefits patients, opening a new chapter in regenerative medicine and therapeutics.

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