title: Emerging cellular and molecular targets in fibrosis: implications for scleroderma pathogenesis and targeted therapy.
abstract: OBJECTIVE
  To summarize the recent advances in understanding the novel cytokine pathways, intracellular signaling molecules, cell-fate decisions, cellular aging and senescence, and the cross-talk of effector cells and the extracellular matrix (ECM) in the pathogenesis of systemic sclerosis (SSc) fibrosis.
  
  
  RESULTS
  Studies from the animal models and human beings implicate novel molecular pathways such as Wnts, the chemokines, chemokine (C-X-C motif) ligand 4 and chemokine (C-C motif) ligand 2, and the lipid mediators lysophosphatidic acid and sphingosine-1-phosphate in the pathogenesis of SSc. These signals, coupled with the mesenchymal cell-fate decisions, contribute to aberrant fibroblast activation and myofibroblast accumulation. The resulting deposition and remodeling of ECM alters the biomechanical environment, and leads to further cross-talk of mechanical signals with biochemical mediators such as focal adhesion kinase, integrin signaling, and Yes-associated protein-transcriptional coactivator with PDZ-binding motif signaling pathways.
  
  
  CONCLUSIONS
  Progress in understanding the cellular, molecular, and biomechanical regulators of fibrosis has led to the identification of novel targets for interrupting the fibrotic process in SSc. Efforts to antagonize cytokine pathways, affect mesenchymal cell fates, attenuate senescence, and clear activated myofibroblasts, along with modifying the ECM mechanical environment, may ultimately lead to effective therapies in SSc.
authors.affiliation: aDivision of Rheumatology, Massachusetts General Hospital, Boston, MA bDivision of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors.forename: Flavia V
authors.initials: FV
authors.lastname: Castelino
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016207:Cytokines