title: Lubricin/Proteoglycan 4 binds to and regulates the activity of Toll-Like Receptors In Vitro.
abstract: Proteoglycan 4 (PRG4/lubricin) is secreted by cells that reside in articular cartilage and line the synovial joint. Lubricin may play a role in modulating inflammatory responses through interaction with CD44. This led us to examine if lubricin could be playing a larger role in the modulation of inflammation/immunity through interaction with Toll-like receptors (TLRs). Human Embryonic Kidney (HEK) cells overexpressing TLRs 2, 4 or 5 and surface plasmon resonance were employed to determine if full length recombinant human lubricin was able to bind to and activate TLRs. Primary human synovial fibroblasts were also examined using flow cytometry and Luminex multiplex ELISA. A rat destabilization model of osteoarthritis (OA) was used to determine if lubricin injections were able to regulate pain and/or inflammation in vivo. Lubricin can bind to and regulate the activity of TLRs, leading to downstream changes in inflammatory signalling independent of HA. We confirmed these findings in vivo through intra-articular injections of lubricin in a rat OA model where the inhibition of systemic inflammatory signaling and reduction in pain were observed. Lubricin plays an important role in regulating the inflammatory environment under both homeostatic and tissue injury states.
authors.affiliation: McCaig Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: S M
authors.initials: SM
authors.lastname: Iqbal
authors.affiliation: McCaig Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Leonard
authors.affiliation: Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: S C
authors.initials: SC
authors.lastname: Regmi
authors.affiliation: Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: D
authors.initials: D
authors.lastname: De Rantere
authors.affiliation: McCaig Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Tailor
authors.affiliation: McCaig Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Ren
authors.affiliation: Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Ishida
authors.affiliation: McCaig Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Cy
authors.initials: C
authors.lastname: Hsu
authors.affiliation: McCaig Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Abubacker
authors.affiliation: Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: D Sj
authors.initials: DS
authors.lastname: Pang
authors.affiliation: McCaig Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: P T
authors.initials: PT
authors.lastname: Salo
authors.affiliation: Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
authors.forename: H J
authors.initials: HJ
authors.lastname: Vogel
authors.affiliation: McCaig Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: D A
authors.initials: DA
authors.lastname: Hart
authors.affiliation: Snyder Institute, Cummings School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: C C
authors.initials: CC
authors.lastname: Waterhouse
authors.affiliation: Faculty of Medicine, Brown University, Providence, Rhode Island, United States.
authors.forename: G D
authors.initials: GD
authors.lastname: Jay
authors.affiliation: McCaig Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.|Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada.|Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada.
authors.forename: T A
authors.initials: TA
authors.lastname: Schmidt
authors.affiliation: McCaig Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: R J
authors.initials: RJ
authors.lastname: Krawetz
mesh_terms: D000328:Adult; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010003:Osteoarthritis / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D051193:Toll-Like Receptors / Q000378:metabolism*; D000099158:Proteoglycan 4
chemical_list: D016207:Cytokines; D006023:Glycoproteins; D006820:Hyaluronic Acid; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051193:Toll-Like Receptors; D000099158:Proteoglycan 4