Cathepsin g degrades synovial fluid lubricin: relevance for osteoarthritis pathogenesis

Abstract

Lubricin (PRG4) is a mucin type protein that plays an important role in maintaining normal joint function by providing lubrication and chondroprotection. Improper lubricin modification and degradation has been observed in idiopathic osteoarthritis (OA), while the detailed mechanism still remains unknown. We hypothesized that the protease cathepsin G (CG) may participate in degrading lubricin in synovial fluid (SF). The presence of endogenous CG in SF was confirmed in 16 patients with knee OA. Recombinant human lubricin (rhPRG4) and native lubricin purified from the SF of patients were incubated with exogenous CG and lubricin degradation was monitored using western blot, staining by Coomassie or Periodic Acid-Schiff in gels, and with proteomics. Full length lubricin (~300 kDa), was efficiently digested with CG generating a 25-kDa protein fragment, originating from the densely glycosylated mucin domain (~250 kDa). The 25-kDa fragment was present in the SF from OA patients, and the amount was increased after incubation with CG. A CG digest of rhPRG4 revealed 135 peptides and 72 glycopeptides, and confirmed that the protease could cleave in different domains of lubricin. Our results suggest that synovial CG may take part in the degradation of lubricin, which could affect the lubrication of OA joints.

Role of Cathepsin G in Rheumatoid Arthritis Diagnosis and Disease Activity Evaluation

“…Despite this lower level of CTSG in RA patients, Gao et al (15) found that the synovial fluid of RA patients has a higher level of CTSG than that of healthy controls, which leads this study to suspect a higher level of CTSG in those patients compared to healthy controls. It is also believed that this increase in CTSG level may be due to the release of a protease enzyme by neutrophils during inflammation (18) .…”

“…Rheumatoid arthritis patients with disease duration less than six months have slightly higher CTSG levels, may due to increased inflammatory immune response in the early stages of RA that stimulates the recruitment and activation of neutrophils in the joints (21) . As part of the immunological response, neutrophils produce and release CTSG (18) . The low levels of CTSG in RA patients with disease duration more than six months may be related to long-term use of medications for RA, which can reduce inflammation and slow disease progression.…”