DDR plays a crucial role in regulating a
DDR2 plays a crucial role in regulating a wide variety of fundamental cellular processes, including cell proliferation, differentiation, and adhesion , , , . The authors revealed compromised cell migration in DDR2-silenced fibroblasts exposed to Ang II, most likely due to the loss of MMP-2. MMP-2 regulates cell migration through cleavage of the surrounding ECM, inducing changes to the AMG-208 and membrane polarity to support directional movement , , . Furthermore, MMP-2 degradation of the basement membrane matrix stimulates fibroblast towards a more synthetic phenotype leading to continued collagen production , . A more thorough evaluation of the role DDR2 plays in fibroblast function is needed to understand Ang II induced cardiac fibrosis and to determine if DDR2 is a suitable treatment strategy.
Translational impact The use of angiotensin receptor blockers such as losartan have been shown to be effective in reducing cardiac fibrosis in a variety of models in animals and humans , , . One limitation of angiotensin receptor blockers is the neuro-humoral negative feedback mechanism that leads to an increase in Ang II along with other angiotensin peptides , , . Increased levels of circulating Ang II results in unopposed stimulation of the AT2 receptor which can lead to potentially unfavorable effects such as apoptosis, pro-inflammatory signal transduction, hypertrophy, or fibrosis , , . A more individualized therapeutic approach will likely be necessary, however, criteria for personalized therapies remains undefined. Evaluating downstream of Ang II activation, George et al. was able to elucidate a mechanism of fibrosis through DDR2 upregulation. Understanding how DDR2 regulates fibroblast wound healing properties, will aid in the development of treatments that target fibrosis independent of the renin–angiotensin system.
Acknowledgements This work was supported by the National Institutes of Health [HL051971, HL075360, GM114833, and GM104357] and the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award [5I01BX000505].
Introduction Collagen is the most abundant protein in the extracellular matrix. Collagen not only provides structural support for cells, tissues, and organs, but also mediates many important biological processes via its interactions with a diverse array of binding partners [, , , , , , ]. Dysregulation of these interactions can lead to significant disease pathology. For example, the interaction between discoidin domain receptor 2 (DDR2) and collagen is aberrantly elevated in osteoarthritis, resulting in induction of matrix metalloproteinase 13 and leading to degradation of articular cartilage [8,9]. A molecular-level understanding of DDR–collagen interactions and how they lead to DDR activation would provide the critical information needed to design selective antagonists for basic biomedical research and potential therapeutics. Herein we review the current efforts of using synthetic peptides and recombinant collagen to study these important interactions.
DDR and collagen
Use of synthetic peptides to study DDR–collagen interactions Designing synthetic peptides to mimic the collagen triple helix has been a rapidly developing field of research over the past few decades. Synthetic collagen-like peptides have been used to study the structure, the stability, and the biological function of collagen. The earliest works focused on synthesizing simple triple-helical tripeptide repeats such as (PPG)  and (POG) . As more techniques to prepare collagen-like peptides and methods to characterize triple helices are being developed, our understanding of collagen and its interactions with other proteins has grown dramatically.