Unraveling the role of discoidin domain receptors as an anti-fibrotic target in various organs: A comprehensive review.

Discoidin domain receptors (DDRs) are a family of tyrosine kinase transmembrane receptors composed of discoidin domain receptor 1 (DDR1) and discoidin domain receptor 2 (DDR2) that interact with components of the extracellular matrix. They are involved in a broad range of important physiological processes, such as extracellular matrix signaling, cell adhesion, cell migration, and tissue fibrosis. DDR1 and DDR2 are expressed in a variety of cell and tissue types, but their expression patterns are variable and dependent on receptor type and physiological environment. Considering that the activation of DDRs mainly depends on the extracellular matrix, namely collagen, this fact therefore establishes DDRs as an attractive anti-fibrotic target with broad therapeutic potential. The role of DDRs has been demonstrated in several types of fibrotic diseases, including liver cirrhosis, renal fibrosis, pulmonary fibrosis, cardiovascular stiffening, and skin hypertrophic scars. The focus of this present review is: a) describing the molecular structure and ligand interactions of DDRs; b) clarifying the expression and tissue functions of DDRs; c) understanding the mechanism of endocytosis and cleavage of the ectodomain; d) detailing collagen remodeling and alignment by DDRs; e) outlining signaling pathways activated by DDRs; f) raising the evidence that DDRs are the target of anti-fibrotic actions in different organs; g) detailing pharmacological efforts that have been made so far to target this subtle anti-fibrotic target.