Fibroblast growth factor 18 (FGF18) belongs to the FGF8 subfamily and plays an important role in the regulation of cell proliferation, cell differentiation and cell migration. It is required for normal ossification and bone development, and also stimulates liver and intestinal proliferation.

(Data source: AlphaFold)

FGF18 is composed of 207 amino acids and is a secreted extracellular protein. The main functional domain is the 28-207 segment, which includes two N-type glycosylation sites and a pair of disulfide bond modifications, and the C-terminus contains a disordered structure.

(Data source: Uniprot)

FGF18 is expressed in embryonic osteogenesis and chondrogenesis and is required for osteogenesis and chondrogenesis. It is mainly expressed in osteogenic mesenchymal cells and differentiated osteoblasts, and actively regulates cell proliferation and differentiation during osteogenesis.

(Data source: Ohbayashi N, et al. Genes Dev. 2002)

In animal studies, FGF18 has been repeatedly shown to have a beneficial effect on osteoarthritis (OA) and promote cartilage healing. Merck, targeting this mechanism of action, was the first to conduct clinical trials of recombinant human FGF18 (rhFGF18, Sprifermin) for the treatment of OA.

(Data source: Clinical trials)

A subsequent 5-year phase II follow-up study after sprifermin treatment showed that at year 2, sprifermin 100 μg treatment significantly increased femoral tibial cartilage thickness compared with placebo, and this was maintained until year 3. Pain improvement persisted until year 5 in the progression-risk group. Sprifermin is effective in increasing knee cartilage thickness with an acceptable safety profile.

(Data source: Eckstein F, et al. Ann Rheum Dis. 2021)

At the same time, a genome-wide association study of a large array of osteoarthritis patients (77,052 cases and 378,169 controls) also confirmed that FGF18 is an effector gene of osteoarthritis.

(Data source: Cai Q, et al. Life Sci. 2020)

However, with the completion of Merck's Phase II sprifermin five-year follow-up study, there has been no plan to continue clinical advancement. It is unclear whether other factors are contributing to this. Other emerging mechanisms of action are also being discovered: for example, the circular RNA circPDE4D regulates FGF18 expression by binding to miR-103a-3p, thereby preventing osteoarthritis. Targeting the circPDE4D-miR-103a-3p-FGF18 axis may provide a potential approach for the treatment of osteoarthritis.

(Data source: Wu Y, et al. Mol Ther. 2021)

Other research directions of FGF18 are relatively scattered: for example, in normal gastric epithelial cells, miR-590-5p inhibits FGF18 expression and blocks FGF18 signal transduction, but in gastric cancer cells, miR-590-5p cannot inhibit FGF18 expression. The activated FGF18 axis triggers MEK-ERK and Smad2/3 signals, leading to abnormal proliferation and invasion of cancer cells.

(Data source: Zhang J, et al. Oncogene. 2019)

promotes the proliferation and metastasis of non-small cell lung cancer cells by stabilizing the deubiquitinase USP10 and activating the β-catenin-FGF18 pathway.

(Data source: Guo K, et al. J Exp Clin Cancer Res)

FGF18 alleviates liver fibrosis through the SMO-LATS1-YAP signaling pathway and may therefore be a potential therapeutic target for liver fibrosis.

(Data source: Tong G, et al. Pharmacol Res. 2022)

Research on FGF18 is mainly focused on the regulation of osteogenesis and cartilage formation. It has potential clinical value in the treatment of skeletal diseases such as cartilage disorders, achondroplasia and bone repair, and has a wide range of effects.