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  • Tranilast Sodium DDR was originally cloned by the group of M


    DDR1 was originally cloned by the group of Michele de Luca, at the time named TrkE. The Genoa-based research team identified the skin, and the keratinocytes in particular, as a major site of DDR1-binding activity [20]. DDR1 is also expressed in kidney, liver and lung (Fig. 2). The functional role of DDR1 in epithelial Tranilast Sodium emerged in 2001 with the generation of homozygous DDR1-null mouse by Vogel et al. [15]. Evidence from that mouse model illustrated the key role of DDR1 as a mediator of the stromal-epithelial interaction. In DDR1−/− mice, the alveolar epithelium of the mammary gland is unable to secrete milk proteins due to increased proliferation (mutant epithelium, analyzed with an antibody to Ki-67, had approximately four to five times more Ki-67-positive cells than WT) and abnormal branching of mammary ducts [15]. This defect was hypothesized to result from sequelae in the underlying stroma. The group also showed that in the developing fat pads of mutant mice, abnormal branching was accompanied by a substantial increase in extracellular matrix (ECM) deposition [15]. At the bottom line, in normal mammary gland development, absence of DDR1 results in epithelial cell hyperproliferation and stromal phenotypical modulation toward an activated myofibroblast phenotype. On a similar note, and apparently paradoxically for a target that is considered anti-fibrotic, DDR1 deficient mice have been shown to exhibit increased collagen deposition in the adventitia. This was observed using Masson\'s trichrome staining, with a higher percentage of collagen fibrils of larger diameter compared with wild-type littermates and a statistically significant increase in the depth of the fibril D-periods [21]. In addition to this role as gatekeeper of the epithelial/mesenchymal crosstalk, DDR1 has an important role within the epidermis, in the intricate and necessary communication between keratinocytes and melanocytes. DDR1 is key in maintaining normal epidermal homeostasis [22]. In in vitro experiments, DDR1 knockdown decreases melanocyte adhesion to type IV collagen (the major component of the basement membrane) and shifts melanocyte localization in a manner similar to CCN3 knockdown [22] (a matricellular protein found to be critical for the spatial localization of melanocytes to the basement membrane). Mechanistic studies have shown DDR1 to be the receptor responsible for CCN3-mediated melanocyte localization [22]. This evidence is supported by studies in lesional and perilesional skin of patients with vitiligo, where dysregulation of the DDR1-CCN3 interaction has been observed [23] and where reduced DDR1 expression has been hypothesized to be implicated in the impaired melanocyte adhesion processes involved in this pathology [24,25]. Further studies by the Vogel group, always using DDR1−/− mice, showed that DDR1 deletion is associated with a severe decrease in auditory function and substantial structural alteration in the inner ear [26].
    Wound healing is an evolutionarily conserved pathophysiological paradigm of fibrogenesis. The wound healing response to injury is known to trigger functional (i.e., proliferative) and phenotypic changes throughout the skin, with involvement of multiple cell types (e.g., fibroblasts, lymphocytes, epithelial and endothelial cells) [27]. Proliferative and phenotypic changes in epithelial and stromal cells respectively, correspond to the epithelial-mesenchymal transition (EMT) and myofibroblast differentiation processes [27]. In minor lesions, EMT enables the epithelium to migrate from the edge of the wound toward the inner lesion to reconstitute the epidermis, whereas myofibroblast differentiation enables a smooth closure of the wound. Those two common processes during wound repair are also found throughout development, inflammation and fibrosis, as well as during tumor progression. Wound healing represents an important pathophysiological context for assessment of the role of DDR1 and DDR2 in fibrotic processes. In excessive scarring, an overexpression of DDR1 in keloid fibroblasts compared with normal human dermal fibroblasts has been documented, suggesting a possible role of DDR1 in keloid pathogenesis. Liposome-encapsulated DDR1-antisense oligonucleotides (ASOs) were shown to decrease over-expression of DDR1 in keloid-derived dermal fibroblasts in vitro, which was associated with downregulation of type I and type III collagen gene expression and ECM production [28]. Moreover, Chin et al. [29], by comparing fetal rat fibroblasts, representing the scarless cutaneous repair phenotype and adult rat fibroblasts, representing the scar forming phenotype, have shown that DDR1, and its downstream adaptor protein Shc, are overexpressed in fetal fibroblasts, suggesting that elevated levels of DDR1 may play a role in scarless tissue regeneration within early gestation fetal fibroblasts [29]. In addition, a pattern of increasing collagen production is observed with increasing gestational age, whereas DDR1 expression progressively decreases (in contrast, levels of DDR2 were constant throughout gestation) [29]. These associative data suggest that differential temporal expression of DDR1 during fetal skin development may play an important role in the ontogeny of scar formation.