title: Cystatin C in cerebrospinal fluid is upregulated in elderly patients with chronic osteoarthritis pain and modulated through matrix metalloproteinase 9-specific pathway.
abstract: OBJECTIVE
  Although high abundant cystatin c (CysC) in cerebrospinal fluid (CSF) is well known, its ambiguous role associated with pain still remains unclear. This study evaluated the effects of intrathecal CysC content from chronic pain caused by osteoarthritis (OA) and the novel relationship with matrix metalloproteinases 2 and 9 (MMP2 and MMP9) in CSF.
  
  
  METHODS
  Samples of CSF were obtained from 8 elderly patients (65 y and above) with OA with lower limb pain for at least 6 months (OA group) and 8 sex-matched and age-matched relatively healthy elderly individuals without any pain problems (control group). The intrathecal CysC, MMP2, and MMP9 were examined by Western blotting. The analysis of CysC cleavage under different conditions was performed through silver staining and using mass-spectroscopy (SELDI-TOF) on 2 groups.
  
  
  RESULTS
  Expression of full-length CysC and pro-MMP2 proteins showed statistically significant upregulation (P=0.0004 vs. 0.03), and expression of MMP9 protein showed downregulation (P=0.007) in the OA group. Both MMP9 and MMP2 initiated the mechanism for full-length CysC cleavage only in the presence of CSF. However, MMP9 showed greater ability than MMP2 for CysC cleavage in control and OA groups in sliver staining. Incubation of CSF with the MMP9 inhibitor led to the suppression of CysC cleavage in SELDI-TOF.
  
  
  CONCLUSIONS
  These findings provide the first in vivo evidence on a relationship between CysC and gelatinases (MMP2 and MMP9), and could facilitate further investigation of novel interactions among these proteins within the proteomics field, especially protein-protein interactions involved in pain.
authors.affiliation: Departments of *Anesthesiology ‡Medical Research, Cathay General Hospital, Taipei †Graduate Institute of Systems Biology and Bioinformatics **Institute of Biomedical Engineering, National Central University ¶Department of Physics, Chung Yuan Christian University, Chungli §Graduate Institute of Biotechnology, College of Bioresources, National Ilan University, Ilan #National Center for Theoretical Science, Shinchu, Taiwan ∥Global Health Education Foundation, Guilford, CT.
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Guo
authors.forename: Cheng-Ta
authors.initials: CT
authors.lastname: Han
authors.forename: Jiun-Lung
authors.initials: JL
authors.lastname: Jung
authors.forename: Wei-Jung
authors.initials: WJ
authors.lastname: Chen
authors.forename: John Jian-Feng
authors.initials: JJ
authors.lastname: Mei
authors.forename: Hoong-Chien
authors.initials: HC
authors.lastname: Lee
authors.forename: Yu-Che
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D059350:Chronic Pain / Q000134:cerebrospinal fluid* / Q000209:etiology*; D055316:Cystatin C / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid*; D008875:Middle Aged; D010003:Osteoarthritis / Q000150:complications*; D015398:Signal Transduction / Q000502:physiology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015854:Up-Regulation / Q000502:physiology
chemical_list: D055316:Cystatin C; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9