Molecular expression patterns in the synovium and their association with advanced symptomatic knee osteoarthritis

Abstract

s u m m a r yObjective: Osteoarthritis (OA) is a major source of knee pain. Mechanisms of OA knee pain are incompletely understood but include synovial pathology. We aimed to identify molecular expression patterns in the synovium associated with symptomatic knee OA. Design: Snap frozen synovia were from people undergoing total knee replacement (TKR) for advanced OA, or from post-mortem (PM) cases who had not sought help for knee pain. Associations with OA symptoms were determined using discovery and validation samples, each comprising TKR and post mortem (PM) cases matched for chondropathy (Symptomatic or Asymptomatic Chondropathy). Associations with OA were determined by comparing age matched TKR and PM control cases. Real-time quantitative PCR for 96 genes involved in inflammation and nerve sensitisation used TaqMan ® Array Cards in discovery and validation samples, and protein expression for replicated genes was quantified using Luminex bead assay. Results: Eight genes were differentially expressed between asymptomatic and symptomatic chondropathy cases and replicated between discovery and validation samples (P<0.05 or >3-fold change). Of these, matrix metalloprotease (MMP)-1 was also increased whereas interleukin-1 receptor 1 (IL1R1) and vascular endothelial growth factor (VEGF) were decreased at the protein level in the synovium of symptomatic compared to asymptomatic chondropathy cases. MMP1 protein expression was also increased in OA compared to PM controls. Conclusion: Associations of symptomatic OA may suggest roles of MMP1 expression and IL1R1 and VEGF pathways in OA pain. Better understanding of which inflammation-associated molecules mediate OA pain should inform refinement of existing therapies and development of new treatments.

Umbilical cord-derived Wharton’s jelly for regenerative medicine applications

“…We also detected expression of vascular endothelial growth factor (VEGF), a signal protein produced by cells to stimulate blood vessel formation. VEGF is involved in bone tissue remodeling and new bone formation and is downregulated in patients with osteoarthritis [25]. Several immunomodulatory cytokines essential for regenerative medicine were identified.…”

Anti-Inflammatory and Chondroprotective Effects of Vanillic Acid and Epimedin C in Human Osteoarthritic Chondrocytes

“…However, previous studies also showed an inverse relation between IL1R1 expression and the amount of IL-1β in OA joints. Wyatt et al showed that IL1R1 was downregulated in OA synovium compared to non-arthritic controls [94]. Moreover, in retinal endothelial cells, IL1R1 expression was downregulated during activation by IL-1β [95].…”

Of mice and men: converging on a common molecular understanding of osteoarthritis

“… 146 Although this observation might be surprising in view of broadly held views that osteoarthritis pain originates from inflammatory processes in the synovium or subchondral bone, emerging molecular data from human tissue also support the notion that cartilage is the principal source of NGF in the osteoarthritis joint. Using agnostic approaches, NGF was not regulated in the synovium of individuals with painful compared with non-painful osteoarthritis, 27 , 79 and it was not found in bone marrow lesions from samples taken at the time of arthroplasty. 147 NGF was found to be regulated in damaged articular cartilage in early microarray studies of osteoarthritis cartilage, 148 and it defines one of seven subsets of chondrocytes identified by single-cell sequencing of human osteoarthritis cartilage.…”

“… 24 , 25 , 26 Additionally, various inflammatory molecules—including cytokines, chemokines, and metalloproteinases—have been measured in osteoarthritis cartilage and synovium. 27 , 28 …”

“…Two mRNA studies of human synovium have been done in individuals stratified by having painful or non-painful osteoarthritis. 27 , 79 One of these studies 27 identified CCL2 as being significantly up-regulated in painful disease. CCR2 antagonism in osteoarthritis pain has been explored clinically (registered with ClinicalTrials.gov , NCT00689273 ), although the results of the study do not appear to have been reported.…”