The interaction of lubricin/proteoglycan 4 (PRG4) with toll-like receptors 2 and 4: an anti-inflammatory role of PRG4 in synovial fluid

Alquraini, Ali; Garguilo, Steven; D’Souza, Gerard G. M.; Zhang, Ling X.; Schmidt, Tannin A.; Jay, Gregory D.; Elsaid, Khaled A.

doi:10.1186/s13075-015-0877-x

Cited by 113 publications

(118 citation statements)

References 48 publications

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“…While PRG4 has been commonly thought of as a bio‐lubricant, a number of additional biological roles have been described. PRG4 directly binds to toll‐like receptors (TLRs) and regulates the inflammatory response both in vitro and in vivo . We therefore chose to examine two common OA treatments, that each partially recapitulate a biomechanical or anti‐inflammatory role of PRG4; HA, which can provide hydrodynamic lubrication to the joint and corticosteroids which regulate inflammation.…”

Section: Resultsmentioning

confidence: 99%

“…PRG4 directly binds to toll-like receptors (TLRs) and regulates the inflammatory response both in vitro and in vivo. 27,31 We therefore chose to examine two common OA treatments, that each partially recapitulate a biomechanical or anti-inflammatory role of PRG4; HA, which can provide hydrodynamic lubrication to the joint and corticosteroids which regulate inflammation. Inclusion of these treatment groups in addition to a direct rescue through administration of rhPRG4 allowed us to determine if regulation of lubrication and/or inflammation impacted the subchondral bone in C57BL/6 and Prg4 −/− mice.…”

Section: Longitudinal Repeated Measures Analysis Of Prg4 −/− Bone Mormentioning

confidence: 99%

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Absence of Proteoglycan 4 (Prg4) Leads to Increased Subchondral Bone Porosity Which Can Be Mitigated Through Intra‐Articular Injection of PRG4

Abubacker

Premnath

Shonak

et al. 2019

Journal Orthopaedic Research

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Proteoglycan 4 (PRG4) is a mucin‐like glycoprotein important for joint health. Mice lacking Prg4 demonstrate degeneration of the cartilage and altered skeletal morphology. The purpose of this study was to examine if Prg4 deficiency leads to subchondral bone defects and if these defects could be mitigated through intra‐articular injection of recombinant human PRG4 (rhPRG4). Mice deficient in Prg4 expression demonstrated increased cartilage thickness and increased subchondral bone porosity compared with C57BL/6 controls. While the porosity of the subchondral bone of Prg4−/− mice decreased over time with maturation, intra‐articular injection of rhPRG4 was able to forestall the increase in porosity. In contrast, neither hyaluronan (HA) nor methylprednisolone injections had beneficial effects on the subchondral bone porosity in the Prg4 knockout mice. Bone marrow progenitor cells from Prg4−/− mice demonstrated reduced osteogenic differentiation capacity at 4 weeks of age, but not at 16 weeks of age. While most studies on PRG4/lubricin focus on the health of the cartilage, this study demonstrates that PRG4 plays a role in the maturation of the subchondral bone. Furthermore, increasing joint lubrication/viscosupplementation through injection of HA or controlling joint inflammation through injection of methylprednisolone may help maintain the cartilage surface, but had no positive effect on the subchondral bone in animals lacking Prg4. Therefore, alterations in the subchondral bone in models with absent or diminished Prg4 expression should not be overlooked when investigating changes within the articular cartilage regarding the pathogenesis of osteoarthritis/arthrosis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2077–2088, 2019

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Section: Resultsmentioning

confidence: 99%

Section: Longitudinal Repeated Measures Analysis Of Prg4 −/− Bone Mormentioning

confidence: 99%

Absence of Proteoglycan 4 (Prg4) Leads to Increased Subchondral Bone Porosity Which Can Be Mitigated Through Intra‐Articular Injection of PRG4

Abubacker

Premnath

Shonak

et al. 2019

Journal Orthopaedic Research

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“…Originally perceived solely as a lubricating molecule in these diverse tissues, we suggest that in addition to reducing friction between biological surfaces a growing body of literature suggests that PRG4 has the ability to interact with immune cells. This implies that PRG4 may play key roles in immunity and/or the regulation of the inflammatory response . In this manuscript, we introduce known lubrication functions of PRG4 and present a hypothesis supported by the literature that PRG4 acts a buffer in the inflammatory response.…”

Section: Introductionmentioning

confidence: 81%

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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“…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 .…”

Section: Discussionmentioning

confidence: 99%

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

Reesink

Watts

Mohammed

et al. 2017

Osteoarthritis and Cartilage

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SUMMARY Objective The goals of this study were (1) to quantify proteoglycan 4 (PRG4) gene expression; (2) to assess lubricin immunostaining; and (3) to measure synovial fluid lubricin concentrations in clinical and experimental models of equine carpal osteoarthritis (OA). Design Lubricin synovial fluid concentrations and cartilage and synovial membrane PRG4 expression were analyzed in research horses undergoing experimental OA induction (n = 8) and in equine clinical patients with carpal OA (n = 58). Lubricin concentrations were measured using a custom sandwich enzyme-linked immunosorbent assay, and PRG4 expression was quantified using qRT-PCR. Lubricin immunostaining was assessed in synovial membrane and osteochondral sections in the experimental model. Results Lubricin concentrations increased in synovial fluid following induction of OA, peaking at 21 days post-operatively in OA joints vs sham-operated controls (331 ± 69 μg/mL vs 110 ± 19 μg/mL, P = 0.001). Lubricin concentrations also increased in horses with naturally occurring OA as compared to control joints (152 ± 32 μg/mL vs 68 ± 4 μg/mL, P = 0.003). Synovial membrane PRG4 expression increased nearly 2-fold in naturally occurring OA (P = 0.003), whereas cartilage PRG4 expression decreased 2.5-fold (P = 0.025). Lubricin immunostaining was more pronounced in synovial membrane from OA joints as compared to controls, with intense lubricin localization to sites of cartilage damage. Conclusions Although PRG4 gene expression decreases in OA cartilage, synovial membrane PRG4 expression, synovial fluid lubricin concentrations and lubricin immunostaining all increase in an equine OA model. Lubricin may be elevated to protect joints from post-traumatic OA.

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The interaction of lubricin/proteoglycan 4 (PRG4) with toll-like receptors 2 and 4: an anti-inflammatory role of PRG4 in synovial fluid

Cited by 113 publications

References 48 publications

Absence of Proteoglycan 4 (Prg4) Leads to Increased Subchondral Bone Porosity Which Can Be Mitigated Through Intra‐Articular Injection of PRG4

Absence of Proteoglycan 4 (Prg4) Leads to Increased Subchondral Bone Porosity Which Can Be Mitigated Through Intra‐Articular Injection of PRG4

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

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

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