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.

Lubricin/proteoglycan 4 increases in both experimental and naturally occurring equine osteoarthritis

“…These findings suggest that lubricin, in addition to enhancing lubrication, may possess anti-inflammatory functions distinct from its lubricating properties in joint trauma. Recently, lubricin has been shown to inhibit synovial inflammation via binding to both the CD44 receptor 42 and Toll-like receptors 2 and 4 43,44 .…”

The Effect of Mechanical Loading on Articular Cartilage

“…During the joint loading, the PGAs are compressed and they permit the distribution of the force on the rest of the joint surface, thereby reducing the pressure on the AC [9]. The joint surface is lined with a glycoprotein called lubricin, produced by both chondrocytes and synoviocytes [10][11][12]. It has boundary lubrication properties, facilitating low friction levels at the interfacing surfaces of AC [10][11][12].…”

“…It has boundary lubrication properties, facilitating low friction levels at the interfacing surfaces of AC [10][11][12]. Loss of lubricin influences the functional properties of synovial joints and could have a role in the pathogenesis of cartilage degeneration [10][11][12].…”

An update on the up and coming therapies to treat osteoarthritis, a multifaceted disease

“…Even more, PRG4 could regulate innate immune response. In fact, PRG4 binds to TLR2 and TLR4 mediating an anti-inflammatory role in synovial cells (134). It is reasonable that PRG4 supplementation could restore rheological and biological status of synovial fluid (135).…”