PRG4

INTRODUCTION: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, and it significantly increases the risk of cardiovascular complications and morbidity, even with appropriate treatment. Tissue remodeling has been a significant topic, while its systematic transcriptional signature remains unclear in AF. OBJECTIVES: Our study aims to systematically investigate the molecular characteristics of AF at the cellular-level. METHODS: We conducted single-nuclei RNA-sequencig (snRNA-seq) analysis using nuclei isolated from the left atrial appendage (LAA) of AF patients and sinus rhythm (SR)...

The identity and origin of the stem/progenitor cells for adult joint cartilage repair remain unknown, impeding therapeutic development. Simulating the common therapeutic modality for cartilage repair in humans, i.e., full-thickness microfracture joint surgery, we combined the mouse full-thickness injury model with lineage tracing and identified a distinct skeletal progenitor cell type enabling long-term (beyond 7 days after injury) articular cartilage repair in vivo. Deriving from a population with active Prg4 expression in adulthood while lacking aggrecan expression, these progenitors proliferate, differentiate to express aggrecan and type II collagen, and predominate in long-term articular cartilage wounds, where they represent the principal repair progenitors in situ under native repair conditions without cellular transplantation...

Proteoglycan 4 (PRG4, lubricin) is a mucin-like glycoprotein present on the ocular surface that has both boundary lubricating and anti-inflammatory properties. Full-length recombinant human PRG4 (rhPRG4) has been shown to be clinically effective in improving signs and symptoms of dry eye disease (DED). In vitro, rhPRG4 has been shown to reduce inflammation-induced cytokine production and NFκB activity in corneal epithelial cells, as well as to bind to and inhibit MMP-9 activity. A different form of recombinant human lubricin (ECF843), produced from the same cell line as rhPRG4 but manufactured using a different process, was recently assessed in a DED clinical trial...

The current work was developed to explore the functions and possible mechanism of PRG4 in cardiac hypertrophy and heart failure. Ang II-stimulated H9c2 cells and AC16 cells were used as in vitro cell models. The binding relation between genes in cells was explored using luciferase reporter assays and RNA immunoprecipitation assay. The cardiac functions of rats received transverse-ascending aortic constriction (TAC) surgery and adeno-associated virus (AAV) injection were examined with echocardiography. The myocardial histological changes were observed using H&E, wheat germ agglutinin, and sirius red staining...

PURPOSE: Place-based measures of structural racism have been associated with breast cancer mortality, which may be driven, in part, by epigenetic perturbations. We examined the association between contemporary redlining, a measure of structural racism at the neighborhood level, and DNA methylation in breast tumor tissue. METHODS: We identified 80 Black and White women diagnosed and treated for a first-primary breast cancer at Emory University Hospitals (2008-2017)...

Suppression of the antitumor cytokine interleukin-24 (IL-24) is critical for the survival of myxoid liposarcoma (MLS) cells. It has been previously demonstrated by the authors that an MLS-specific chimeric oncoprotein, translocated in liposarcoma-CCAAT/enhancer-binding protein homologous protein (TLS-CHOP), supresses IL24 mRNA expression via induction of proteoglycan 4 (PRG4) to sustain MLS cell proliferation. However, IL-24 has also been revealed to be suppressed by the ubiquitin-proteasome system in human ovarian and lung cancer cells...

The onset and progression of human inflammatory joint diseases are strongly associated with the activation of resident synovium/infrapatellar fat pad (IFP) pro-inflammatory and pain-transmitting signaling. We recently reported that intra-articularly injected IFP-derived mesenchymal stem/stromal cells (IFP-MSC) acquire a potent immunomodulatory phenotype and actively degrade substance P (SP) via neutral endopeptidase CD10 (neprilysin). Our hypothesis is that IFP-MSC robust immunomodulatory therapeutic effects are largely exerted via their CD10-bound small extracellular vesicles (IFP-MSC sEVs) by attenuating synoviocyte pro-inflammatory activation and articular cartilage degradation...

The superficial zone cells in mandibular condylar cartilage are proliferative. The present purpose was to delineate the relation of calcium-sensing receptor (CaSR) and parathyroid hormone-related peptide nuclear localization sequence (PTHrP87-139 ), and their role in the proliferation behaviors of the superficial zone cells. A gain- and loss-of-function strategy were used in an in vitro fluid flow shear stress (FFSS) model and an in vivo bilateral elevation bite model which showed mandibular condylar cartilage thickening...

BACKGROUND: The influence of genetics and environment on the association of the plasma proteome with body mass index (BMI) and changes in BMI remain underexplored, and the links to other omics in these associations remain to be investigated. We characterized protein-BMI trajectory associations in adolescents and adults and how these connect to other omics layers. METHODS: Our study included two cohorts of longitudinally followed twins: FinnTwin12 ( N =651) and the Netherlands Twin Register (NTR) ( N =665)...

TGF-β is a prominent anabolic signaling molecule associated with synovial joint health. Recent work has uncovered mechanochemical mechanisms that activate the latent form of TGF-β (LTGF-β) in the synovial joint-synovial fluid (SF) shearing or cartilage compression-pointing to mechanobiological phenomena, whereby enhanced TGF-β activity occurs during joint stimulation. Here, we implement computational and experimental models to better understand the role of mechanochemical-activated TGF-β (aTGF-β) in regulating the functional biosynthetic activities of synovial joint tissues...

BACKGROUND: Genetically modified mice are the most useful tools for investigating the gene functions in articular cartilage biology and the pathogenesis of osteoarthritis. The Aggrecan CreERT2 mice are one of the most reported mouse lines used for this purpose. The Prg4 (proteoglycan 4) gene encodes the lubricin protein and is expressed selectively in chondrocytes located at the superficial layer of the articular cartilage. While the Prg4 GFPCreERT2 knock-in inducible-Cre transgenic mice were generated a while ago, so far, few studies have used this mouse line to perform gene functional studies in cartilage biology...

Mass spectrometry (MS) based proteomics is widely used for biomarker discovery. However, often, most biomarker candidates from discovery are discarded during the validation processes. Such discrepancies between biomarker discovery and validation are caused by several factors, mainly due to the differences in analytical methodology and experimental conditions. Here, we generated a peptide library which allows discovery of biomarkers in the equal settings as the validation process, thereby making the transition from discovery to validation more robust and efficient...

Meniscus injuries are extremely common with approximately one million patients undergoing surgical treatment annually in the U.S. alone, but no regenerative therapy exist. Previously, we showed that controlled applications of connective tissue growth factor (CTGF) and transforming growth factor beta 3 (TGFβ3) via fibrin-based bio-glue facilitate meniscus healing by inducing recruitment and stepwise differentiation of synovial mesenchymal stem/progenitor cells. Here, we first explored the potential of genipin, a natural crosslinker, to enhance fibrin-based glue's mechanical and degradation properties...

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) usually occurs in the second and third trimesters. The disease's etiology and diagnostic criteria are currently unknown. Based on a sequence window to obtain all theoretical fragment ions (SWATH) proteomic approach, this study sought to identify potential proteins in placental tissue that may be involved in the pathogenesis of ICP and adverse fetal pregnancy outcomes. METHODS: The postpartum placental tissue of pregnant women with ICP were chosen as the case group (ICP group) (subdivided into mild ICP group (MICP group) and severe ICP group (SICP group)), and healthy pregnant women were chosen as the control group (CTR)...

PRG4 is an extracellular matrix protein that maintains homeostasis through its boundary lubricating and anti-inflammatory properties. Altered expression and function of PRG4 have been associated with joint inflammatory diseases, including osteoarthritis. Here we show that mast cell tryptase β cleaves PRG4 in a dose- and time-dependent manner, which was confirmed by silver stain gel electrophoresis and mass spectrometry. Tryptase-treated PRG4 results in a reduction of lubrication. Compared to full-length, cleaved PRG4 further activates NF-κB expression in cells overexpressing TLR2, -4, and -5...

In vitro models allow for the study of developmental processes outside of the embryo. To gain access to the cells mediating digit and joint development, we identified a unique property of undifferentiated mesenchyme isolated from the distal early autopod to autonomously re-assemble forming multiple autopod structures including: digits, interdigital tissues, joints, muscles and tendons. Single-cell transcriptomic analysis of these developing structures revealed distinct cell clusters that express canonical markers of distal limb development including: Col2a1 , Col10a1 , and Sp7 (phalanx formation), Thbs2 and Col1a1 (perichondrium), Gdf5 , Wnt5a , and Jun (joint interzone), Aldh1a2 and Msx1 (interdigital tissues), Myod1 (muscle progenitors), Prg4 (articular perichondrium/articular cartilage), and Scx and Tnmd (tenocytes/tendons)...

Frictional properties of cartilage resurfacing implants should be sufficiently low to limit damaging of the opposing cartilage during articulation. The present study determines if native lubricious molecule proteoglycan 4 (PRG4) can adsorb onto a layer-by-layer bioinspired coating composed of poly-l-lysine (PLL) and dopamine modified hyaluronic acid (HADN) and thereby can reduce the friction between implant and articular cartilage. An ELISA was developed to quantify the amount of immobilized human recombinant (rh)PRG4 after exposure to the PLL-HADN coating...

In recent years, engineering biomimetic cellular microenvironments have been a top priority for regenerative medicine. Collagen II, which is arranged in arches, forms the predominant fiber network in articular cartilage. Due to the shortage of suitable microfabrication techniques capable of producing 3D fibrous structures, in vitro replication of the arch-like cartilaginous tissue constitutes one of the major challenges. Hence, in the present study, we report a 3D bioprinting approach for fabricating arch-like constructs using two types of bioinks, gelatin methacryloyl(GelMa) and silk fibroin-gelatin(SF-G)...

Induced pluripotent stem cells (iPSCs) are a promising resource for allogeneic cartilage transplantation to treat articular cartilage defects that do not heal spontaneously and often progress to debilitating conditions, such as osteoarthritis. However, to the best of our knowledge, allogeneic cartilage transplantation into primate models has never been assessed. Here, we show that allogeneic iPSC-derived cartilage organoids survive and integrate as well as are remodeled as articular cartilage in a primate model of chondral defects in the knee joints...

Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed to be caused by the wearing and tearing of articular cartilage, but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues, which leads to the histological and structural changes of the joint and ends up with the whole tissue dysfunction. Currently, there is no cure for OA, partly due to a lack of comprehensive understanding of the pathological mechanism of the initiation and progression of the disease...