title: Cysteine cathepsins and extracellular matrix degradation.
abstract: BACKGROUND
  Cysteine cathepsins are normally found in the lysosomes where they are involved in intracellular protein turnover. Their ability to degrade the components of the extracellular matrix in vitro was first reported more than 25years ago. However, cathepsins were for a long time not considered to be among the major players in ECM degradation in vivo. During the last decade it has, however, become evident that abundant secretion of cysteine cathepsins into extracellular milieu is accompanying numerous physiological and disease conditions, enabling the cathepsins to degrade extracellular proteins.
  
  
  METHODS
  In this review we will focus on cysteine cathepsins and their extracellular functions linked with ECM degradation, including regulation of their activity, which is often enhanced by acidification of the extracellular microenvironment, such as found in the bone resorption lacunae or tumor microenvironment. We will further discuss the ECM substrates of cathepsins with a focus on collagen and elastin, including the importance of that for pathologies. Finally, we will overview the current status of cathepsin inhibitors in clinical development for treatment of ECM-linked diseases, in particular osteoporosis.
  
  
  CONCLUSIONS
  Cysteine cathepsins are among the major proteases involved in ECM remodeling, and their role is not limited to degradation only. Deregulation of their activity is linked with numerous ECM-linked diseases and they are now validated targets in a number of them. Cathepsins S and K are the most attractive targets, especially cathepsin K as a major therapeutic target for osteoporosis with drugs targeting it in advanced clinical trials.
  
  
  CONCLUSIONS
  Due to their major role in ECM remodeling cysteine cathepsins have emerged as an important group of therapeutic targets for a number of ECM-related diseases, including, osteoporosis, cancer and cardiovascular diseases. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
authors.affiliation: Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia; Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova cesta 39, SI-1000 Ljubljana, Slovenia. Electronic address: marko.fonovic@ijs.si.
authors.forename: Marko
authors.initials: M
authors.lastname: Fonović
authors.affiliation: Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia; Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova cesta 39, SI-1000 Ljubljana, Slovenia; Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia. Electronic address: boris.turk@ijs.si.
authors.forename: Boris
authors.initials: B
authors.lastname: Turk
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000737:chemistry / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D013379:Substrate Specificity
chemical_list: D002403:Cathepsins; D003545:Cysteine
keywords: Cathepsin; Collagen; Extracellular matrix; Glycosaminoglycan; Lysosome; Osteoporosis