For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
16
views
32
references
 Top references
cited by
43
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      393
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      RANTES/CCL5 Induces Collagen Degradation by Activating MMP-1 and MMP-13 Expression in Human Rheumatoid Arthritis Synovial Fibroblasts

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Regulated on activation, normal T expressed, and secreted (RANTES)/CC ligand 5 (CCL5) participates in rheumatoid arthritis (RA) pathogenesis by facilitating leukocyte infiltration, however, its other pathological functions are not fully defined in RA. In the present study, we evaluated the effect of RANTES/CCL5 on tissue degrading enzymes matrix metalloproteinase-1 (MMP-1) and MMP-13 expression and its contribution to the progressive joint damage by RA synovial fibroblasts (RASFs). Our results showed that RANTES/CCL5 dose dependently induced MMP-1 and MMP-13 expression in monolayers and three-dimensional (3D) micromass of human RASFs, which correlated with an increase in collagenase activity. This activation by RANTES/CCL5 was observed in RASF, but not in osteoarthritis SFs (OASFs). Evaluation of the signaling events showed that RANTES/CCL5 selectively activated PKCδ, JNK, and ERK proteins to induce MMP expression in human RASFs. Pretreatment with a functional antagonist (Met-RANTES) or heparinase III [an enzyme that selectively digests heparan sulfate proteoglycans (HSPGs)] completely abrogated RANTES/CCL5-induced MMP-1 and MMP-13 expression. Interestingly, the inhibition of RANTES/CCL5 using small-interfering RNA approach reduced the ability of interleukin-1β (IL-1β) to induce MMP-1 and MMP-13 expression, asserting its mediatory role in tissue remodeling. In the inhibitor study, only the selective inhibition of HSPGs or PKCδ, ERK, and JNK markedly inhibited RANTES/CCL5-induced MMP-1 and MMP-13 production. Circular dichroism spectroscopy results demonstrated the degradation of collagen triple-helical structure upon exposure to the conditioned media from RANTES/CCL5 stimulated RASFs, which was reverted by a broad-spectrum MMP inhibitor (GM6001). These findings suggest that RANTES/CCL5 not only upregulates MMP-1 and MMP-13 expression by partly utilizing HSPGs and/or PKCδ-JNK/ERK pathways but also mediates IL-1β-induced MMP-1 and MMP-13 expression.

          Related collections

          Most cited references32

          • Record: found
          • Abstract: not found
          • Article: not found

          Chemokines: a new classification system and their role in immunity.

          A Zlotnik, O Yoshie (2000)
          Article 0 comments Cited 503 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Matrix metalloproteinases: role in arthritis.

            Peter S Burrage, Kimberlee S Mix, Constance Brinckerhoff (2006)
            The irreversible destruction of the cartilage, tendon, and bone that comprise synovial joints is the hallmark of both rheumatoid arthritis (RA) and osteoarthritis (OA). While cartilage is made up of proteoglycans and type II collagen, tendon and bone are composed primarily of type I collagen. RA is an autoimmune disease afflicting numerous joints throughout the body; in contrast, OA develops in a small number of joints, usually resulting from chronic overuse or injury. In both diseases, inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) stimulate the production of matrix metalloproteinases (MMPs), enzymes that can degrade all components of the extracellular matrix. The collagenases, MMP-1 and MMP-13, have predominant roles in RA and OA because they are rate limiting in the process of collagen degradation. MMP-1 is produced primarily by the synovial cells that line the joints, and MMP-13 is a product of the chondrocytes that reside in the cartilage. In addition to collagen, MMP-13 also degrades the proteoglycan molecule, aggrecan, giving it a dual role in matrix destruction. Expression of other MMPs such as MMP-2, MMP-3 and MMP-9, is also elevated in arthritis and these enzymes degrade non-collagen matrix components of the joints. Significant effort has been expended in attempts to design effective inhibitors of MMP activity and/or synthesis with the goal of curbing connective tissues destruction within the joints. To date, however, no effective clinical inhibitors exist. Increasing our knowledge of the crystal structures of these enzymes and of the signal transduction pathways and molecular mechanisms that control MMP gene expression may provide new opportunities for the development of therapeutics to prevent the joint destruction seen in arthritis.
            Article 0 comments Cited 292 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis.

              Y Yoshihara, H Nakamura, T Hayakawa … (2000)
              Matrix metalloproteinases (MMPs) are expressed in joint tissues of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The objective of this study was to define the steady state levels of seven different MMPs and two tissue inhibitors of metalloproteinases (TIMPs) as well as the potential metalloproteinase activity in the synovial fluid (SF) to provide more insight into the role of MMPs in cartilage destruction in RA and OA. Levels of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, TIMP-1, and TIMP-2 in SF aspirated from knee joints of 97 patients with RA and 103 patients with OA were measured by the corresponding one step sandwich enzyme immunoassays. Proteolytic activity of MMPs in these SFs was examined in an assay using [(3)H]carboxymethylated transferrin substrate in the presence of inhibitors of serine and cysteine proteinases after activation with p-aminophenylmercuric acetate (APMA). Destruction of RA knee joints was radiographically evaluated. Levels of MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 were significantly higher in RA SF than in OA SF. MMP-7 and MMP-13 were detectable in more than 45% of RA SFs and in less than 20% of OA SFs, respectively. Among the MMPs examined, MMP-3 levels were extremely high compared with those of other MMPs. Direct correlations were seen between the levels of MMP-1 and MMP-3 and between those of MMP-8 and MMP-9 in RA SF. Although the levels of MMP-1 and MMP-3 increased even in the early stage of RA, those of MMP-8 and MMP-9 were low in the early stage and increased with the progression of RA. Molar ratios of the total amounts of the MMPs to those of the TIMPs were 5.2-fold higher in patients with RA than in OA, which was significant. APMA-activated metalloproteinase activity in SF showed a similar result, and a direct correlation was seen between the molar ratios and the activity in RA SF. Our results show that high levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and TIMP-1 are present in RA SF and suggest that once these MMPs are fully activated, they have an imbalance against TIMPs, which may contribute to the cartilage destruction in RA.
              Article 0 comments Cited 117 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Solomon A. Agere: URI : http://frontiersin.org/people/u/449419
                Jeffery M. Watson: URI : http://frontiersin.org/people/u/474839
                Salahuddin Ahmed: URI : http://frontiersin.org/people/u/35167
                Journal
                Journal ID (nlm-ta): Front Immunol
                Journal ID (iso-abbrev): Front Immunol
                Journal ID (publisher-id): Front. Immunol.
                Title: Frontiers in Immunology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-3224
                Publication date (Electronic): 18 October 2017
                Publication date Collection: 2017
                Volume: 8
                Electronic Location Identifier: 1341
                Affiliations
                [1] 1Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University , Spokane, WA, United States
                [2] 2Department of Chemistry and Biochemistry, Gonzaga University , Spokane, WA, United States
                [3] 3Division of Rheumatology, University of Washington School of Medicine , Seattle, WA, United States
                Author notes

                Edited by: Jixin Zhong, Case Western Reserve University, United States

                Reviewed by: Xuhui Feng, Indiana University System, United States; Junjie Zhang, University of Southern California, United States; Yinghong Hu, Emory University, United States

                *Correspondence: Salahuddin Ahmed, salah.ahmed@ 123456wsu.edu

                †Present address: Salahuddin Ahmed, Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington, United States.

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                DOI: 10.3389/fimmu.2017.01341
                PMC ID: 5651228
                PubMed ID: 29093715
                SO-VID: 4c1bdfe4-0017-42a4-9b00-a32cb7322a02
                Copyright © Copyright © 2017 Agere, Akhtar, Watson and Ahmed.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 14 July 2017
                Date accepted : 03 October 2017
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 39, Pages: 12, Words: 7692
                Categories
                Subject: Immunology
                Subject: Original Research

                ScienceOpen disciplines: Immunology
                Keywords: rheumatoid arthritis,synovial fibroblasts,regulated on activation,normal t expressed,secreted/cc ligand 5,matrix metalloproteinases,heparan sulfate proteoglycans
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: rheumatoid arthritis, synovial fibroblasts, regulated on activation, normal t expressed, secreted/cc ligand 5, matrix metalloproteinases, heparan sulfate proteoglycans

                Comments

                Comment on this article

                scite_

                Similar content393

                See all similar

                Cited by42

                See all cited by

                Most referenced authors456

                See all reference authors