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.

Background: MicroRNAs (miRNAs) are identified as crucial gene regulators in response to myocardial infarction (MI). However, the overall relationships between miRNAs and the gene targets which contribute to the cellular phenotypes in MI are not fully elucidated. To make a better understanding towards functional roles of miRNAs in MI, useful information was mined through bioinformatic techniques. Method: MI-related miRNAs were retrieved from publications, and PicTar, TargetScanS, and miRanda programs were used to predict their gene targets. Gene ontology (GO) and pathway analyses of gene targets were applied to uncover functional roles of miRNAs. The miRNA-gene networks were illustrated by Pajek tool. Finally, validation experiments were performed towards two important miRNAs in the networks. Result: Up to 119 MI-related miRNAs were retrieved from publications. GO and pathway analyses for their predicted gene targets demonstrated that these dysregulated miRNAs were enriched in cardiovascular-related phenotypes. Through illustrating miRNA-gene networks, overall relationships between miRNAs and gene targets were detected especially in processes of apoptosis and angiogenesis. Moreover, experimental data supported bioinformatic predictions that miR-106b served as an anti-apoptotic modulator through inhibition of p21 expression and miR-15b displayed anti-angiogenesis activity. Conclusion: The miRNAs played essential roles in pathological processes of MI. Further, miR-106b and miR-15b maybe mediated as robust regulators in apoptosis or angiogenesis following MI, respectively.

BackgroundInflammation is associated with the onset and progression of osteoarthritis in multiple joints. It is well known that mechanical properties differ between different joints, however, it remains unknown if the inflammatory process is similar/distinct in patients with hip vs. knee OA. Without complete understanding of the role of any specific cytokine in the inflammatory process, understanding the ‘profile’ of inflammation in a given patient population is an essential starting point. The aim of this study was to identify serum cytokine profiles in hip Osteoarthritis (OA), and investigate the association between cytokine concentrations and clinical measurements within this patient population and compare these findings to knee OA and healthy control cohorts.MethodsIn total, 250 serum samples (100 knee OA, 50 hip OA and 100 control) and 37 synovial fluid samples (8 knee OA, 14 hip OA and 15 control) were analyzed using a multiplex ELISA based approach. Synovial biopsies were also obtained and examined for specific cytokines. Pain, physical function and activity within the hip OA cohort were examined using the HOOS, SF-36, HHS and UCLA outcome measures.ResultsThe three cohorts showed distinct serum cytokine profiles. EGF, FGF2, MCP3, MIP1α, and IL8 were differentially expressed between hip and knee OA cohorts; while FGF2, GRO, IL8, MCP1, and VEGF were differentially expressed between hip OA and control cohorts. Eotaxin, GRO, MCP1, MIP1β, VEGF were differentially expressed between knee OA and control cohorts. EGF, IL8, MCP1, MIP1β were differentially expressed in synovial fluid from a sub-set of patients from each cohort. Specifically within the hip OA cohort, IL-6, MDC and IP10 were associated with pain and were also found to be present in synovial fluid and synovial membrane (except IL-6) of patients with hip OA.ConclusionOA may include different inflammatory subtypes according to affected joints and distinct inflammatory processes may drive OA in these joints. IL6, MDC and IP10 are associated with hip OA pain and these proteins may be able to provide additional information regarding pain in hip OA patients.Electronic supplementary materialThe online version of this article (10.1186/s12891-018-1955-4) contains supplementary material, which is available to authorized users.

BackgroundResident macrophages in OA synovial tissue contribute to synovitis through pro-inflammatory mediators driving cartilage loss. What remains unknown is how these macrophages interact with synovial mesenchymal progenitor cells (sMPCs) in the joint. sMPCs have the potential to undergo chondrogenesis, but for yet unknown reasons, this ability is decreased in OA patients. In this study, we sought to identify if alteration of macrophage activity regulates the chondrogenic capacity of sMPCs.MethodsAn explant model was developed using human synovium obtained from normal individuals and OA patients. These explants were subjected to macrophage depletion and/or cytokine stimulation in order to regulate/deplete the residing macrophage population. Supernatant was collected following a 12-day treatment phase and subjected to inflammatory secretome analysis. sMPCs from the explants were subsequently placed under 21-day chondrogenic differentiation and levels of type II collagen (Col2a), Aggrecan (Acan), and Sox9 gene expression was quantified.ResultsInflammatory secretome analysis from OA patients revealed the presence of pro-inflammatory analytes following pro- and anti-inflammatory cytokine stimulation and/or macrophage depletion. Additionally, chondrogenic differentiation of sMPCs was heterogeneously impacted across all OA patients following pro-/anti-inflammatory cytokine stimulation and/or macrophage depletion.ConclusionTissue resident synovial macrophages can regulate the chondrogenic differentiation of sMPCs after cytokine stimulation in a patient specific manner. The secretion profile of OA synovium was also responsive to cytokine stimulation and/or macrophage depletion as observed by the largely pro-inflammatory milieu upregulated following cytokine stimulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12950-016-0120-9) contains supplementary material, which is available to authorized users.