title: Administration of cathepsin B inhibitor CA-074Me reduces inflammation and apoptosis in polymyositis.
abstract: BACKGROUND
  Polymyositis (PM) cause pain and weakness of muscle, even threatens patient's lives, but the etiology and pathogenesis of it remains partially understood. Previous studies have proved Cathepsin B (CB) was strongly stained in muscle tissues of PM patients. But no further studies were performed to investigate the role of CB in PM.
  
  
  OBJECTIVE
  To investigate the protective effects of CB inhibitor CA-074Me in PM.
  
  
  METHODS
  CB expression, inflammation and apoptosis were analyzed in muscle tissues from patients with PM. Guinea pigs were inoculated intraperitoneally with Coxsackie virus B1 (CVB1) and were then immunized with completely emulsified 0.6ml rabbit muscle homogenates in Freund's Complete Adjuvant (FCA) once a week for consecutive three weeks. The effects of CB inhibitor CA-074Me on CB expression, inflammation and apoptosis were then investigated. Inflammation was assessed by histological examination. Both immunohistochemistry and western blot were used to determine the protein expression. The mRNA levels of CB were measured by Real-Time RT-PCR. The apoptosis was determined by TUNEL assay.
  
  
  RESULTS
  In patients with PM, the protein levels of CB were significantly up-regulated in muscle tissues compared with healthy controls, which correlated with increases in inflammation score and apoptotic rate in PM patients. Consistently, the expression of CB, inflammation score, CD8(+) T-cell, CD68(+) cell, tumor necrosis factor-alpha (TNF-α) infiltration and apoptotic rate were significantly increased in the guinea-pig model of CVB1-induced polymyositis. Administration of CA-074Me reduced CB expression, decreased inflammation score and attenuated apoptosis in muscle tissues of the guinea-pig model of CVB1-induced polymyositis. The inhibitory effect of CA-074Me on apoptosis was associated with down-regulation of Bax expression and consequent increase in the ratio of Bcl-2/Bax. However, CA-074Me had effect not on CD8(+) T-cells infiltrations but on CD68(+) cells and TNF-α(+) cells infiltrations in the guinea-pig model of CVB1-induced polymyositis.
  
  
  CONCLUSIONS
  This study confirms up-regulation of CB in PM patients and demonstrates that inhibition of CB provides protective effects in a guinea pig model of CVB1-induced PM. Thus, CB will be an important therapeutic target for PM.
authors.affiliation: Department of Dermatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Feng
authors.forename: Liyan
authors.initials: L
authors.lastname: Ni
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism; D017285:Polymyositis / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002401:Cathepsin B; D004151:Dipeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; C400541:CA 074 methyl ester; C067980:CD68 antigen, human; D000097382:CD68 Molecule
keywords: Apoptosis; Bcl-2/Bax; CA-074Me; Cathepsin B; Polymyositis