Involvement of the p38 MAPK-NF-κB Signal Transduction Pathway and COX-2 in the Pathobiology of Meniscus Degeneration in Humans

Osteoarthritis and Cartilage

Vanderman

et al. 2014

Objective Meniscus injury increases the risk of osteoarthritis; however, the biologic mechanism remains unknown. We hypothesized that pro-inflammatory stimulation of meniscus would increase production of matrix-degrading enzymes, cytokines and chemokines which cause joint tissue destruction and could contribute to osteoarthritis development. Design Meniscus and cartilage tissue from healthy tissue donors and total knee arthroplasties was cultured. Primary cell cultures were stimulated with pro-inflammatory factors [IL-1β, IL-6, or fibronectin fragments (FnF)] and cellular responses were analyzed by real-time PCR, protein arrays and immunoblots. To determine if NF-κB was required for MMP production, meniscus cultures were treated with inflammatory factors with and without the NF-κB inhibitor, hypoestoxide. Results Normal and osteoarthritic meniscus cells increased their MMP secretion in response to stimulation, but specific patterns emerged that were unique to each stimulus with the greatest number of MMPs expressed in response to FnF. Meniscus collagen and connective tissue growth factor gene expression was reduced. Expression of cytokines (IL-1α, IL-1β, IL-6), chemokines (IL-8, CXCL1, CXCL2, CSF1) and components of the NF-κB and tumor necrosis factor (TNF) family were significantly increased. Cytokine and chemokine protein production was also increased by stimulation. When primary cell cultures were treated with hypoestoxide in conjunction with pro-inflammatory stimulation, p65 activation was reduced as were MMP-1 and MMP-3 production. Conclusions Pro-inflammatory stimulation of meniscus cells increased matrix metalloproteinase production and catabolic gene expression. The meniscus could have an active biologic role in osteoarthritis development following joint injury through increased production of cytokines, chemokines, and matrix-degrading enzymes.

Section: Discussionmentioning

confidence: 99%

Pro-inflammatory stimulation of meniscus cells increases production of matrix metalloproteinases and additional catabolic factors involved in osteoarthritis pathogenesis

Stone

Osteoarthritis and Cartilage

Vanderman

et al. 2014

“…A recent study found evidence for p38 activation in ruptured menisci [26]. Another recent report found that MMP-1 production by OA synovial fibroblasts stimulated with adiponectin required p38 activity [27].…”

Section: Map Kinase Function With Relevance To Osteoarthritismentioning

confidence: 99%

Mitogen-activated protein kinases as therapeutic targets in osteoarthritis

Current Opinion in Rheumatology

Erickson

Long

2008

116

110

Purpose of review-The mitogen-activated protein (MAP) kinases are intracellular signaling proteins which play a central role in controlling the activity of pathways that regulate production and activity of multiple mediators of joint tissue destruction. The therapeutic potential of MAP kinase inhibition in osteoarthritis was reviewed. Summary-MAP kinase inhibition has the potential to slow disease progression in osteoarthritis and also might reduce pain; however, safety concerns have limited the use of general MAP kinase inhibitors in humans. Further understanding of the function of specific isoforms of the MAP kinases as well as upstream and downstream effectors may lead to the development of more specific inhibitors with less toxicity that could eventually be used as structure-modifying drugs for OA. Recent findings-Results

“…Smad1 linker region phosphorylation at serines of PXSP motifs by MAPKs has been shown to limit nuclear accumulation, reduce transcription activity, and induce Smad1 degradation in developmental models [16, 23–25]. This potential mechanism for OP1 resistance had not been studied in the meniscus, but many of the inflammatory cytokines associated with the torn or degenerative menisci, including IL1 and FnF, activate the MAPKs [44], and phosphorylated p38 MAPK has been identified histologically from torn menisci [45]. In articular cartilage, IL1β has been shown to increase Smad1 linker region phosphorylation through p38 MAPK [21, 31].…”

Section: Discussionmentioning

confidence: 99%

Reduced response of human meniscal cells to Osteogenic Protein 1 during osteoarthritis and pro-inflammatory stimulation

Vanderman

Osteoarthritis and Cartilage

Chubinskaya

et al. 2016

Objective Many cell types lose responsiveness to anabolic factors during inflammation and disease. Osteogenic Protein 1 (OP1/BMP7) was evaluated for the ability to enhance extracellular matrix synthesis in healthy and OA meniscus cells. Mechanisms of cell response to OP1 were explored. Design Meniscus and cartilage tissues from healthy tissue donors and osteoarthritis patients undergoing total knee arthroplasties were acquired. Primary cell cultures were stimulated with OP1 and/or inflammatory factors (IL1α, IL1β, or fibronectin fragments (FnF)) and cellular responses were analyzed by RT-qPCR and immunoblots. Frozen section immunohistochemistry was conducted to assess OP1 and receptor proteins in normal and OA meniscus. Results OP1 treatment of normal meniscus cells resulted in significant, dose-dependent increases in ACAN (aggrecan) and COL2A1, and decreased MMP13 gene transcription, while only ACAN was upregulated (p<0.01) at the highest dose of OP1 in OA meniscus cells. OP1 induced significantly more ACAN gene transcription in normal meniscus than normal articular cartilage (p=0.05), and no differences between normal and OA cartilage were detected. Receptor expression and kinetics of canonical signaling activation were similar between normal and OA specimens. Normal meniscus cells treated with inflammatory factors were refractory to OP1 stimulation. Smad1 phosphorylation at an inhibitory site was induced (p=0.01 for both normal and OA meniscus) by inflammatory cytokine treatment. Conclusions The meniscus demonstrates resistance to OP1 stimulation in OA and in the presence of inflammatory mediators. MAPK-mediated Smad1 linker phosphorylation is a possible mediator of the loss of anabolic extracellular matrix production in the inflammatory cytokine affected meniscus.