Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments

Homandberg, Gene A.

doi:10.2741/homandberg

Cited by 111 publications

(22 citation statements)

References 125 publications

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“…Chondrocyte expression and release of Wnt5a was stimulated by FN-f, a matrix fragment found in OA cartilage and synovial fluid that has been shown to stimulate catabolic signaling (reviewed in 23, 24 ). Wnt5a was found to activate β-catenin independent Wnt signaling pathways, including activation of CaMKII, JNK, p38, ERK1/2, p65 and Akt.…”

Section: Discussionmentioning

confidence: 99%

Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes

Huang

Chubinskaya

Liao

et al. 2017

Osteoarthritis and Cartilage

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Objective Aberrant Wnt signaling may contribute to osteoarthritis (OA) but the Wnt family members involved have not been fully identified. The purpose of this study was to investigate the role of Wnt5a as a potential mediator of cartilage destruction in OA. Design Immunohistochemistry to detect Wnt5a was performed using normal and OA human articular cartilage. Cultured normal human chondrocytes were treated with fibronectin fragments (FN-f) as a catabolic stimulus or recombinant Wnt5a protein with or without pretreatment using a panel of signaling inhibitors. Expression of Wnt5a, anabolic genes and catabolic genes were determined by quantitative real-time PCR. Production of Wnt5a protein and matrix metalloproteinases (MMPs) as well as activation of signaling proteins were analyzed by immunoblotting. Results Wnt5a was present in human articular cartilage with OA changes and its expression and secretion were increased in FN-f stimulated chondrocytes. FN-f stimulated Wnt5a production through the JNK and ERK pathways. Wnt5a reduced aggrecan gene expression after 48 hours of treatment. Wnt5a seemed to promote MMP1, -3, and -13 expression as well as MMP1 and MMP13 protein production in normal human chondrocytes. Wnt5a inhibitor peptides did not affect FN-f induced MMP production. Wnt5a activated β-catenin independent signaling including calmodulin-dependent protein kinase II (CaMKII), JNK, p38, ERK1/2, p65 and Akt. Inhibition of JNK, p38, ERK, PI-3 kinase and CaMKII by specific signaling inhibitors suppressed Wnt5a mediated MMP1 and MMP13 production. Conclusions Wnt5a is present in human OA cartilage and can promote chondrocyte catabolic activity through non-canonical Wnt signaling, which suggests a potential role in OA.

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Section: Discussionmentioning

confidence: 99%

Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes

Huang

Chubinskaya

Liao

et al. 2017

Osteoarthritis and Cartilage

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“…Proteomic analysis has indicated that both the EDA domain and the III-1c peptide could be released from the matrix by MMP2 [26]. Although the presence of fibronectin fragments has been documented in injured and disease tissue [6], [55]–[57], little is known about their specific sequences and concentrations within the local microenvironment. Force-induced unfolding of the FnIII-1 domain has been shown to expose cryptic activity regulating fibronectin polymerization [9], [58], [59], cell growth [60], [61] and skeletal muscle contraction [60], [61].…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Innate Immune Response by Fibronectin: Synergism between the III-1 and EDA Domains

et al. 2014

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Fibronectin is a critical component of the extracellular matrix and alterations to its structure will influence cellular behavior. Matrix fibronectin is subjected to both mechanical and biochemical regulation. The Type III domains of fibronectin can be unfolded in response to increased cellular contractility, included or excluded from the molecule by alternative splicing mechanisms, or released from the matrix by proteolysis. Using Inflammatory Cytokine microarrays we found that the alternatively spliced fibronectin Type III domain, FnEDA, and the partially unfolded III-1 domain, FnIII-1c, induced the expression of a multitude of pro-inflammatory cytokines in human dermal fibroblasts, most notably CXCL1-3, IL-8 and TNF-α. FnIII-1c, a peptide representing an unfolded intermediate structure of the first Type III domain has been shown to initiate the toll-like receptor-4 (TLR4)-NFκB-dependent release of cytokines from human dermal fibroblasts (You, et al., J. Biol. Chem., 2010). Here we demonstrate that FnIII-1c and the alternatively spliced FnEDA domain induce a TLR4 dependent activation of p38 MAP kinase and its downstream effector, MAPKAP Kinase-2 (MK-2), to regulate cytokine expression in fibroblasts. RT-qPCR analysis indicated that the p38-MK-2 pathway regulates IL-8 mRNA stability. Interestingly, addition of FnIII-1c and FnEDA synergistically enhanced TLR4-dependent IL-8 release. These data indicate that Fn contains two Type III domains which can activate TLR signaling to induce an inflammatory response in fibroblasts. Furthermore, our data identifies the NF-κB and p38/MK2 signaling pathways as transducers of signals initiated in response to structural changes in fibronectin.

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“…Matrix fragments are known to exert destructive effects in OA pathophysiology and regulate tissue remodelling events in chondrocytes [28]. In OA cartilage, exogenous cytokines increase iNOS expression and NO production leading to proteoglycan degradation [29,30].…”

Section: Discussionmentioning

confidence: 99%

Low oxygen tension increased fibronectin fragment induced catabolic activities - response prevented with biomechanical signals

et al. 2013

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IntroductionThe inherent low oxygen tension in normal cartilage has implications on inflammatory conditions associated with osteoarthritis (OA). Biomechanical signals will additionally contribute to changes in tissue remodelling and influence the inflammatory response. In this study, we investigated the combined effects of oxygen tension and fibronectin fragment (FN-f) on the inflammatory response of chondrocytes subjected to biomechanical signals.MethodsChondrocytes were cultured under free-swelling conditions at 1%, 5% and 21% oxygen tension or subjected to dynamic compression in an ex vivo 3D/bioreactor model with 29 kDa FN-f, interleukin-1beta (IL-1β) and/or the nitric oxide synthase (NOS) inhibitor for 6 and 48 hours. Markers for catabolic activity (NO, PGE2), tissue remodelling (GAG, MMPs) and cytokines (IL-1β, IL-6 and TNFα) were quantified by biochemical assay. Aggrecan, collagen type II, iNOS and COX-2 gene expression were examined by real-time quantitative PCR. Two-way ANOVA and a post hoc Bonferroni-corrected t-test were used to analyse data.ResultsBoth FN-fs and IL-1β increased NO, PGE2 and MMP production (all P < 0.001). FN-f was more active than IL-1β with greater levels of NO observed at 5% than 1% or 21% oxygen tension (P < 0.001). Whilst FN-f reduced GAG synthesis at all oxygen tension, the effect of IL-1β was significant at 1% oxygen tension. In unstrained constructs, treatment with FN-f or IL-1β increased iNOS and COX-2 expression and reduced aggrecan and collagen type II (all P < 0.001). In unstrained constructs, FN-f was more effective than IL-1β at 5% oxygen tension and increased production of NO, PGE2, MMP, IL-1β, IL-6 and TNFα. At 5% and 21% oxygen tension, co-stimulation with compression and the NOS inhibitor abolished fragment or cytokine-induced catabolic activities and restored anabolic response.ConclusionsThe present findings revealed that FN-fs are more potent than IL-1β in exerting catabolic effects dependent on oxygen tension via iNOS and COX-2 upregulation. Stimulation with biomechanical signals abolished catabolic activities in an oxygen-independent manner and NOS inhibitors supported loading-induced recovery resulting in reparative activities. Future investigations will utilize the ex vivo model as a tool to identify key targets and therapeutics for OA treatments.

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Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments

Cited by 111 publications

References 125 publications

Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes

Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes

Regulation of the Innate Immune Response by Fibronectin: Synergism between the III-1 and EDA Domains

Low oxygen tension increased fibronectin fragment induced catabolic activities - response prevented with biomechanical signals

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