Fibromodulin, a Multifunctional Matricellular Modulator

Abstract

Fibromodulin (FMOD) is an archetypal member of the class II small leucine-rich proteoglycan family. By directly binding to extracellular matrix structural components, such as collagen and lysyl oxidase, FMOD regulates collagen cross-linking, packing, assembly, and fibril architecture via a multivalent interaction. Meanwhile, as a pluripotent molecule, FMOD acts as a ligand of various cytokines and growth factors, especially those belonging to the transforming growth factor (TGF) β superfamily, by interacting with the corresponding signaling molecules involved in cell adhesion, spreading, proliferation, migration, invasion, differentiation, and metastasis. Consequently, FMOD exhibits promigratory, proangiogenic, anti-inflammatory, and antifibrogenic properties and plays essential roles in cell fate determination and maturation, progenitor cell recruitment, and tissue regeneration. The multifunctional nature of FMOD thus enables it to be a promising therapeutic agent for a broad repertoire of diseases, including but not limited to arthritis, temporomandibular joint disorders, caries, and fibrotic diseases among different organs, as well as to be a regenerative medicine candidate for skin, muscle, and tendon injuries. Moreover, FMOD is also considered a marker for tumor diagnosis and prognosis prediction and a potential target for cancer treatment. Furthermore, FMOD itself is sufficient to reprogram somatic cells into a multipotent state, creating a safe and efficient cell source for various tissue reconstructions and thus opening a new avenue for regenerative medicine. This review focuses on the recent preclinical efforts bringing FMOD research and therapies to the forefront. In addition, a contemporary understanding of the mechanism underlying FMOD’s function, particularly its interaction with TGFβ superfamily members, is also discussed at the molecular level to aid the discovery of novel FMOD-based treatments.

Fibromodulin facilitates the osteogenic effect of Masquelet's induced membrane by inhibiting the TGF-β/SMAD signaling pathway

“…Subsequently, a literature review was performed on these genes, revealing that FMOD serves as a multifunctional regulator of the extracellular matrix, exerts anti-inflammatory effects, and facilitates angiogenesis. 26 The results of KEGG enrichment analysis revealed that TGF-β signaling was the downstream pathway of FMOD, and the correspondence between the FMOD and TGF-β signaling pathways is shown in the KEGG chord diagram (Fig. 3E and F).…”

Quantitative N-Glycoproteomic Analysis of Cattle-Yak and Yak Longissimus Thoracis

“…As a member of the leucine-rich small proteoglycan family, fibromodulin has an important role in collagen fibril production. Recently, a study has reported that fibromodulin can regulate collagen cross-linking, accumulation, and assembly and the collagen fibril structure through multivalent interactions . In addition, its interaction with lysyl oxidase helps to regulate the ECM composition, thus providing a relaxed environment to regulate cell renewal .…”

“…Recently, a study has reported that fibromodulin can regulate collagen cross-linking, accumulation, and assembly and the collagen fibril structure through multivalent interactions. 31 In addition, its interaction with lysyl oxidase helps to regulate the ECM composition, thus providing a relaxed environment to regulate cell renewal. 32 In other words, fibromodulin profoundly influences the structural composition of the ECM.…”

Fibromodulin overexpression drives oral squamous cell carcinoma via activating downstream EGFR signaling

“…As an ECM protein, Fibromodulin (FMOD) plays a role in multiple cellular biological events, including ECM remodeling, collagen fibrogenesis, dedifferentiation, and inflammation. 19 , 20 Beyond that, current evidence suggests that FMOD acts as diagnostic and prognostic biomarkers in cancers and exerts oncogenic roles by regulating cell apoptosis, angiogenesis, and migration. 20 , 21 Mayr and colleagues have reported that FMOD is a tumor-associated antigen in chronic lymphocytic leukemia via facilitating the expansion of specific CD8 + autologous T lymphocytes.…”