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

Abstract

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.

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

“…Many of these degenerative changes in joint tissues are also reproduced in animal models of OA, allowing specific testing of particular parameters or components. [133,134] High molecular weight HA is an efficient visco-supplement but in combination with PRG4 improved boundary lubrication has been demonstrated. [129,130,132] Articular chondrocytes are also responsive to these inflammatory mediators but to a lesser extent.…”

“…[131] In vitro approaches specifically examining features of meniscal pathobiology have also demonstrated focal tissue changes in response to stimulation by IL-1 and TNFα. [133] PRG4 like HA also has anti-inflammatory [133] and cell directive properties. [129] Just as PGs are now appreciated to be multi-functional proteins with additional ECM stabilizing and space-filling supportive roles, functional roles for visco-supplement polymers other than in boundary lubrication and joint articulation also need to be considered.…”

“…[102] Alkyl HA derivatives are also effective at inhibiting MMP production and activation. [133] A multifunctional visco-supplement approach to the treatment of OA is a novel strategy which deserves further evaluation in the experimental systems described above and in vivo. [96,100,103,137,138] Thus novel formulations of viscosupplements incorporating HA and PRG4 are worthy of further evaluation and may have a global joint protective effect in OA.…”

“…[129] Just as PGs are now appreciated to be multi-functional proteins with additional ECM stabilizing and space-filling supportive roles, functional roles for visco-supplement polymers other than in boundary lubrication and joint articulation also need to be considered. [133,134] High molecular weight HA is an efficient visco-supplement but in combination with PRG4 improved boundary lubrication has been demonstrated. [133] PRG4 like HA also has anti-inflammatory [133] and cell directive properties.…”

“…[133,134] High molecular weight HA is an efficient visco-supplement but in combination with PRG4 improved boundary lubrication has been demonstrated. [133] PRG4 like HA also has anti-inflammatory [133] and cell directive properties. High molecular weight HA has chondro-protective properties through its ability to inhibit degradative MMP production by chondrocytes stimulated with inflammatory mediators [135] and also modulate synoviocytes within the joint.…”