title: New frontiers in fibrotic disease therapies: The focus of the Joan and Joel Rosenbloom Center for Fibrotic Diseases at Thomas Jefferson University.
abstract: Fibrotic diseases constitute a world-wide major health problem, but research support remains inadequate in comparison to the need. Although considerable understanding of the pathogenesis of fibrotic reactions has been attained, no completely effective therapies exist. Although fibrotic disorders are diverse, it is universally appreciated that a particular cell type with unique characteristics, the myofibroblast, is responsible for replacement of functioning tissue with non-functional scar tissue. Understanding the cellular and molecular mechanisms responsible for the creation of myofibroblasts and their activities is central to the development of therapies. Critical signaling cascades, initiated primarily by TGF-β, but also involving other cytokines which stimulate pro-fibrotic reactions in the myofibroblast, offer potential therapeutic targets. However, because of the multiplicity and complex interactions of these signaling pathways, it is very unlikely that any single drug will be successful in modifying a major fibrotic disease. Therefore, we have chosen to examine the effectiveness of administration of several drug combinations in a mouse pneumoconiosis model. Such treatment proved to be effective. Because fibrotic diseases that tend to be chronic, are difficult to monitor, and are patient variable, implementation of clinical trials is difficult and expensive. Therefore, we have made efforts to identify and validate non-invasive biomarkers found in urine and blood. We describe the potential utility of five such markers: (i) the EDA form of fibronectin (Fn(EDA)), (ii) lysyl oxidase (LOX), (iii) lysyl oxidase-like protein 2 (LoxL2), (iv) connective tissue growth factor (CTGF, CCNII), and (v) the N-terminal propeptide of type III procollagen (PIIINP).
authors.affiliation: Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States; Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States. Electronic address: Joel.Rosenbloom@jefferson.edu.
authors.forename: Joel
authors.initials: J
authors.lastname: Rosenbloom
authors.affiliation: Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States; Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States.
authors.forename: Shumei
authors.initials: S
authors.lastname: Ren
authors.affiliation: Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States; Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Macarak
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000097:blood / Q000652:urine; D000818:Animals; D015415:Biomarkers / Q000097:blood* / Q000652:urine*; D055513:Connective Tissue Growth Factor / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D005353:Fibronectins / Q000097:blood / Q000652:urine; D006801:Humans; D051379:Mice; D010446:Peptide Fragments / Q000097:blood / Q000652:urine; D011009:Pneumoconiosis / Q000097:blood* / Q000473:pathology / Q000652:urine*; D011347:Procollagen / Q000097:blood / Q000652:urine; D051127:Scavenger Receptors, Class E / Q000097:blood
chemical_list: D015415:Biomarkers; C526317:CCN2 protein, human; D005353:Fibronectins; C495137:OLR1 protein, human; D010446:Peptide Fragments; D011347:Procollagen; D051127:Scavenger Receptors, Class E; C000593306:fibronectinEDA, human; C041876:procollagen Type III-N-terminal peptide; D055513:Connective Tissue Growth Factor; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human
keywords: Biomarkers; Combination drug therapy; Fibrosis; Fibrotic disease; Myofibroblast; Transforming growth factor beta (TGF-β)