Degradation of proteoglycan 4/lubricin by cathepsin S: Potential mechanism for diminished ocular surface lubrication in Sjögren's syndrome

Regmi, Suresh C.; Samsom, Michael; Heynen, Miriam; Jay, Gregory D.; Sullivan, Benjamin D.; Srinivasan, Sruthi; Caffery, Barbara; Jones, Lyndon; Schmidt, Tannin A.

doi:10.1016/j.exer.2017.05.006

Cited by 39 publications

(44 citation statements)

References 28 publications

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“…Thus, do pro‐inflammatory cytokines directly affect expression of PRG4 or they induce protease which in turn cleave and or shed off PRG4 altering its functionality? Previous studies demonstrated that PRG4 is a substrate of MMP‐1, MMP‐7, neutrophil elastase, plasmin, cathepsin B, and cathepsin S . Although the degradation of PRG4 by cathepsin S was associated with its diminished lubrication, we propose that cleaved PRG4 fragments may interact with cell surface receptors of corneal and conjunctival epithelium cells would affect the inflammatory response.…”

Section: Transcriptional and Proteolytic Regulation Of Prg4mentioning

confidence: 64%

“…Previous studies demonstrated that PRG4 is a substrate of MMP‐1, MMP‐7, neutrophil elastase, plasmin, cathepsin B, and cathepsin S . Although the degradation of PRG4 by cathepsin S was associated with its diminished lubrication, we propose that cleaved PRG4 fragments may interact with cell surface receptors of corneal and conjunctival epithelium cells would affect the inflammatory response. Co‐incubations of these proteases with PRG4 followed by N‐terminal labeling of neo‐N‐termini (cleavage site labeling) with formaldehyde and an in‐gel trypsin digest experiment run on a liquid chromatography (LC) tandem mass spectrometer (MS/MS) would reveal the precise cleavage sites of PRG4 by each of these proteases.…”

Section: Transcriptional and Proteolytic Regulation Of Prg4mentioning

confidence: 64%

“…Prg4 −/− mice also present with changes to the articular cartilage, but also present with increased damage to the ocular surface staining, thus suggesting that PRG4 may play a key role in ocular surface boundary lubrication, and may prevent corneal damage under normal homeostatic conditions . Furthermore, in vivo pre‐clinical animal studies and ex vivo studies on human tissues have demonstrated that altered expression and/or function of PRG4 has been associated with acute and chronic diseases including osteoarthritis (OA), rheumatoid arthritis (RA), Sjogren syndrome, atherosclerosis, and pericarditis . In most of these previous studies, the function by which PRG4 promotes tissue homeostasis or its absence contributes to increased tissue damage has been through a reduction in friction.…”

Section: Introductionmentioning

confidence: 99%

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Proteoglycan 4: From Mere Lubricant to Regulator of Tissue Homeostasis and Inflammation

et al. 2018

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Proteoglycan 4 (PRG4), first identified in synovial fluid, is an extracellular matrix structural protein in the joint implicated in reducing shear at the cartilage surface as well as controlling adhesion-dependent synovial growth and regulating bulk protein deposition onto the cartilage. However, recent evidence suggests that it can bind to and effect downstream signaling of a number of cell surface receptors implicated in regulating the inflammatory response. Therefore, we pose the hypothesis: Does PRG4 regulate the inflammatory response and maintain tissue homeostasis? Based on these novel findings implicating PRG4 as an inflammatory signaling molecule, we will present and discuss several hypotheses regarding potential mechanisms by which PRG4 may be able to regulate inflammation. If future studies can demonstrate that PRG4 is a potent inflammatory mediator, this will change current paradigms in the musculoskeletal and ophthalmological fields regarding the how the inflammatory microenvironment is regulated in these tissues and potentially others.

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Section: Transcriptional and Proteolytic Regulation Of Prg4mentioning

confidence: 64%

Section: Transcriptional and Proteolytic Regulation Of Prg4mentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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Proteoglycan 4: From Mere Lubricant to Regulator of Tissue Homeostasis and Inflammation

et al. 2018

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“…Recombinant human Lubricin (rhPRG4) expressed from CHO cells were purified as described elsewhere 2,50 . Bovine lubricin (bPRG4) was purified using CsCl gradient and anion exchange chromatography, and purity confirmed with SDS-PAGE/western blot and mass spectrometry as described elsewhere 51 .…”

Section: Samples Human Tissues and Cellsmentioning

confidence: 99%

Core-2O-glycans are required for galectin-3 interaction with the osteoarthritis related protein lubricin

Ali

et al. 2019

Preprint

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Author contributions: SA planned and executed the glycomic analysis, KT and LA planned and executed the glycoproteomic analysis, SH performed ELISA analysis, SR performed SPR analysis, YM and JH designed the recombinant expression and experiments executed by YM. OR, LB, RK, TS and TE were responsible for control and patient sample collection. TS and GJ contributed with design and provision of rhPRG4 for the analysis, MS and AK participated in planning and supervision of galectin-3 experiments. SF, KT and NK performed the writing with input from all contributors. NK coordinated and directed the research. All authors signed off on the final version.ABSTRACT Synovial fluid lubricin (proteoglycan 4) is a mucin-type O-linked glycosylated (60% of the mass) biological lubricant involved in osteoarthritis (OA) development. Lubricin has been reported to be cross-linked by synovial galectin-3 on the lubricating articular surface. Here, we confirm that binding to galectin-3 depended on core-2 O-linked glycans, where surface plasmon resonance of a recombinant lubricin (rhPRG4) devoid of core-2 structures lacked binding capacity to recombinant galectin-3. Both galectin-3 levels and interactions with synovial lubricin were found to be decreased in late-stage OA patients coinciding with an increase of truncated and less sialylated core 1 O-glycans. These data suggest a defect cross-linking of surface active molecules in OA and provides novel insights into OA molecular pathology.

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“…As such, lubricin degradation may play a role in OA associated inflammation. A limited number of proteases have been identified to degrade lubricin, among the more studied are lysosomal cysteine proteases cathepsin B, S, L and neutrophil elastase 26,30,31 . Cathepsin G (CG) is one of the major neutrophil serine proteases that is synthesised in bone marrow and subsequently stored in the azurophil granules of polymorphonuclear neutrophils 32,33 .…”

Section: Introductionmentioning

confidence: 99%

Cathepsin g degrades synovial fluid lubricin: relevance for osteoarthritis pathogenesis

Huang

Thomsson

Jin

et al. 2019

Preprint

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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.

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Degradation of proteoglycan 4/lubricin by cathepsin S: Potential mechanism for diminished ocular surface lubrication in Sjögren's syndrome

Cited by 39 publications

References 28 publications

Proteoglycan 4: From Mere Lubricant to Regulator of Tissue Homeostasis and Inflammation

Proteoglycan 4: From Mere Lubricant to Regulator of Tissue Homeostasis and Inflammation

Core-2O-glycans are required for galectin-3 interaction with the osteoarthritis related protein lubricin

Cathepsin g degrades synovial fluid lubricin: relevance for osteoarthritis pathogenesis

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