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Fibroblast biology Signals targeting the synovial fibroblast in arthritis

  • 1, 2, 3,
  • 1, 3,
  • 1,
  • 1, 2,
  • 1, 3 and
  • 1
Arthritis Research & Therapy20002:348

  • Received: 24 February 2000
  • Accepted: 27 April 2000
  • Published:


Fibroblast-like cells in the synovial lining (type B lining cells), stroma and pannus tissue are targeted by many signals, such as the following: ligands binding to cell surface receptors; lipid soluble, small molecular weight mediators (eg nitric oxide [NO], prostaglandins, carbon monoxide); extracellular matrix (ECM)-cell interactions; and direct cell-cell contacts, including gap junctional intercellular communication. Joints are subjected to cyclic mechanical loading and shear forces. Adherence and mechanical forces affect fibroblasts via the ECM (including the hyaluronan fluid phase matrix) and the pericellular matrix (eg extracellular matrix metalloproteinase inducer [EMMPRIN]) matrices, thus modulating fibroblast migration, adherence, proliferation, programmed cell death (including anoikis), synthesis or degradation of ECM, and production of various cytokines and other mediators [1]. Aggressive, transformed or transfected mesenchymal cells containing proto-oncogenes can act in the absence of lymphocytes, but whether these cells represent regressed fibroblasts, chondrocytes or bone marrow stem cells is unclear.


  • fibroblast
  • rheumatoid arthritis
  • synovial membrane

Soluble mediators binding to cell surface receptors

Cytokine network and signal transduction

Cytokines bind to their receptors, activating signal transduction pathways such as adenylate cyclase/cAMP, phospholipase C/inositol trisphosphate, and Ca2+ and tyrosine kinases. Cytokines can stimulate random migration (chemokinesis), guided fibroblast migration along a concentration gradient (chemokinesis; Table 1) [2,3,4,5,6,7,8,9,10,11,12,13,14,15] and/or fibroblast proliferation (Table 2) [16,17,18,19,20,21,22,23,24,25]. Regulation of fibroblast migration and proliferation is not straightforward; the effect may be indirect or dependent on concentration and the cytokine network. Some cytokines act as competence rather than progression factors, some lack secretory signals, and some must be processed and released from the pericellular matrix or basement membranes (eg transforming growth factor beta [TGF-β ] binding to chondroitin or the keratan sulfate of biglycan, decorin and fibromodulin, or basic fibroblast growth factor and platelet derived growth factor binding to the heparin sulfate of glypican, perlecan and syndecan).

Matrix deposition

The TGF-β family forms an important group of growth factors, consisting of three isoforms in man, and is important for matrix deposition because it modulates fibroblast recruitment and proliferation. This growth factor also stimulates production of collagens, proteoglycans, elastin, fibronectin, tenascin and thrombospondin, diminishes production of extracellularly active neutral endoproteinases belonging to the matrix metalloproteinase (MMP) and serine proteinase families, and stimulates production of endogenous MMP inhibitors (tissue inhibitor of metallo-proteinase [TIMP]) and serpins (plasminogen activator inhibitor-1). Other profibrotic, collagen synthesis stimulating cytokines include endothelin, interleukin (IL)-1 and mast cell tryptase. Interferons and IL-4 decrease collagen synthesis. In addition to IL-4, `biologicals' such as humanized anti-TGF-β antibodies and recombinant human interferons are, accordingly, being tested as a treatment for fibrotic diseases.

Matrix degradation

Fibroblasts produce proteolytic enzymes (in particular, MMPs). MMPs now comprise a group of 18 different enzymes in man, including the classic fibroblast collagenase MMP-1 (collagenase-1), the mesenchymal form of MMP-8 (collagenase-2) and MMP-13 (collagenase-3). MMP-8 was known as neutrophil collagenase until it was found to be produced by tumor necrosis factor α (TNF-α) stimulated fibroblasts, for example, although in a less glycosylated form (50 kDa instead of 75 kDa) [26]. Co-localization of TNF and its receptors in synovial tissue and at the cartilage-pannus junction may play a role in the pathogenesis of rheumatoid arthritis [27]. Fibroblasts produce TIMPs (1-4), which were previously called human fibroblast collagenase inhibitors. TIMP-1 is induced by inflammatory cytokines IL-1 and TNF-α, but also by TGF-β, progesterone and estrogen. IL-6, interestingly, does not seem to stimulate the production of collagenase, but is a potent inducer of TIMP-1.
Table 1

Soluble mediators regulating fibroblast migration



Cellular or tissue source




Macrophage, activated monocyte, B cell, T cell, fibroblast




T cell, mast cell, bone marrow stromal cell




Platelet, macrophage, endothelial cell, skeletal muscle cell, fibroblast, vascular smooth



muscle cell, glial cell, type I astrocyte, myoblast, kidney, epithelial cell, mesangial cell




Platelet, macrophage, T cell, skeletal muscle cell, fibroblast




Brain, retina, bone matrix, endothelial cell, macrophage




Granulocyte, ectodermal cell, kidney, duodenal gland, platelet



Neurokinin A

Nerve cell




Nerve cell



Endothelin-1 and -3

Endothelial cell, macrophage, fibroblast, many other cells



β -thromboglobulin

Platelet, megakaryocyte



Platelet factor 4

Platelet, megakaryocyte




Myeloid cells, from transported LTA4 in many nonmyeloid and nonhematopoietic cells




Fibroblast, skeletal cell, liver, endothelial cell, T cell







Matrix proteins














Serum derived

Complement (C5)



chemotactic factor


for fibroblasts




T lymphocyte, NK cell (interferon-γ), all cells (interferon-α)







Neutrophil factor



+, Stimulation; -, inhibition. bFGF, basic fibroblast growth factor; CGRP, calcitonin gene-related peptide; ECM, extracellular matrix; EGF, epidermal growth factor; IGF, insulin-like growth factor; IL, interleukin; LTA, leukotriene A; LTB, leukotriene B; NK, natural killer; PDGF, platelet derived growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor.

Table 2

Soluble mediators regulating fibroblast proliferation



Examples of cellular and tissue source




Alveolar macrophage




Brain, retina, bone matrix, endothelial cells, macrophage















EGF and TGF-α

Granulocyte, ectodermal cells, kidney, duodenal gland, platelet




T lymphocyte, NK cell




Fibroblast, skeletal cell, liver, endothelial cell, T cell







IL-1α and IL-β

Monocyte/macrophage, Langerhans cell, other dendritic cells, T lymphocyte, B lymphocyte,


NK cell, large granular lymphocyte, vascular endothelial cell, smooth muscle cell, fibroblast,


thymic epithelial cell, astrocyte, microglia, keratinocyte, chondrocyte



IL-1 inhibitor





Platelet, macrophage, endothelial cell, fibroblasts, vascular smooth cells, glial cell, type I astrocyte,



kidney, epithelial cell, mesangial cells




T cell




Platelets, macrophage, T cell, skeletal muscle cell, fibroblast






+, Stimulation; -, inhibition. aFGF, acidic fibroblast growth factor; AMDGF, alveolar macrophage-derived growth factor; bFGF, basic fibroblast growth factor; CTAP, connective tissue-activating peptide; EGF, epidermal growth factor; IGF, insulin-like growth factor; IL, interleukin; NK, natural killer; PDGF, platelet derived growth factor; PMN, polymorphonuclear cell; TCDGF, T cell derived growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor.

Lipid soluble mediators penetrating the cell membrane

NO is a freely diffusible radical gas, which is a product of the catalytic conversion of L-arginine to L-citrulline by nitric oxide synthases (NOS) (EC via the chemical reaction between the guanidino-nitrogen of L-arginine and dioxygen. The activity of the inducible NO synthase (iNOS) requires pro-inflammatory cytokines such as IL-1 and TNF-α for upregulation of mRNA and protein. The activity of iNOS, in turn, is under strict control of nicotinamide adenine dinucleotide phosphate (NADPH), flavine adenidine dinucleotide, flavin mononucleotide, heme and 5,6,7,8-tetrahydrobiopterin for activity [28]. The iNOS is highly expressed in the rheumatoid synovium, particularly in synovial fibroblasts [29,30]. The mRNA initiation site of the iNOS gene is preceded by a promoter sequence box, along with two distinct regions upstream containing consensus sequences for the binding of various transcription factors. Region 1 contains lipopolysaccharide responsive elements such as the binding sites for nuclear factor-1, IL-6 and NF-κ B, indicating a locus for LPS induced synthesis of iNOS. Region 2 contains motifs for interferon gamma (IFN-γ)-regulated transcription factors but does not directly regulate induction of iNOS; instead, it subserves region 1. LPS therefore stimulates iNOS synthesis directly, and IFN-γ acts in synergy with LPS to augment iNOS synthesis and NO production. This synergy also extends to the cytokines IL-1 and TNF-α, which, in combination with IFN-γ, augment the synthesis of iNOS and NO [31]. Apoptosis induced by NO is associated with nuclear p53 protein expression in cultured human fibroblasts [32]. NO can also induce the synthesis and activity of cyclo-oxygenase (COX)-2 and hemeoxygenase (HO)-1.

Prostaglandin H2 (PGH2) synthase (EC has two activities, COX and peroxidase, and occurs in two isoforms, known as COX-1 and COX-2 [33]. The inducible COX-2 mRNA and protein are stimulated largely by the same factors as iNOS, such as IL-1, TNF-α and IFN-γ [34]. The promoter region of COX-2 contains binding sites for NF-κ B, NF-IL6 and two motifs for IFN-γ activatedsequences [34]. PGE2 and PGE1 inhibit cytokine-induced metalloproteinase expression in human synovial fibroblasts [35]. COX inhibition conversely enhances the production of pro-MMP-1 in human rheumatoid synovial fibroblasts [36]. PGE2 also enhances the synthesis of IL-8 and IL-6, but inhibits granulocyte-macrophage colony-stimulating factor production by IL-1 stimulated synovial fibroblasts [37].

Carbon monoxide is produced by two homologous microsomal HO (EC 1.14.93) isoenzymes: inducible HO-1 (heat shock protein-32) and constitutively expressed HO-2. The latter is widely expressed in fibroblasts, and HO-1 can be induced in these and other cell types by hypoxia and free radicals [38]. HO-1 prevents cell death by regulating intracellular iron levels. HO functions by cleaving heme to biliverdin and carbon monoxide, in the presence of NADPH and NADPH-cytochrome P450, with equimolar iron released from the heme as a co-product [39]. There is a regulatory loop between iron metabolism and the NO pathway: intracellular ferric iron (Fe3+) levels can significantly decrease iNOS mRNA transcription, and iron chelating agents like desferrioxamine can increase iNOS transcription and NO production [40]. NO itself, conversely, can directly control intracellular iron metabolism by activating the iron-regulatory protein involved in ferritin translocation. Therefore, the interplay between iNOS and HO-1 activities may have far-reaching consequences in situations characterized by oxidative stress.

Extracellular matrix, and integrin and nonintegrin receptors

The ECM-cell interactions are coupled to cytoskeletal elements, such as α -actinin, talin and tensin, and affect various tyrosine kinases, for example focal adhesion kinases, Src (the protein product of the src gene of the Rous sarcoma virus) family kinases and Crk (the protein product of the crk gene from chicken retroviruses CT10 and ASV-1). Focal adhesion kinases provide a potent anoikis resistance factor [41], anoikis referring to apoptosis caused by loss of ECM-cell adhesion. ECM-fibroblast interactions are important because the synovial lining cells and the pannus are subjected to shear stress. Synovial cells are also subjected to cyclic mechanical loading during the movement of the joint.

The synovial ECM provides hydraulic resistance, preventing rapid seepage of synovial fluid out of the joint cavity, and modifies the traffic of macromolecules. It may trap antigens, which contribute to inflammation. The three main classes of synovial structural polymers are collagen (scaffolding), extrafibrillar glycosaminoglycans/proteoglycans and structural glycoproteins. Under normal circumstances, collagen is hidden in a matrix created by the latter two classes. Fibronectin guides fibroblast migration as an immobilized substrate and attractant in the leading edge of the pannus (haptotaxis) [42]. The extra domain-A fibronectin isoform is associated with the activated, transformed state of type B lining cells [43]. The interaction between connecting sequence-1 fibronectin (or vascular cell adhesion molecule-1) and α 4β 1 (very late activation antigen-4) may play a role in the proliferation of synovial lining and lymphocyte migration [44]. EMMPRIN (Mr = 58 000) is an integral plasma membrane glycoprotein of the pericellular matrix belonging to the immunoglobulin superfamily, previously referred to as tumor-cell derived collagenase stimulatory factor. It is identical to the M6 leukocyte activation antigen, and highly homologous to rat OX-47 or CE9, mouse basigin or gp42, and chicken HT-7 or neurothelin molecules. Reciprocal immunoprecipitation, cell surface crosslinking and immunofluorescence co-localization experiments demonstrated that EMMPRIN can form a complex with integrins α 3β 1 and α 6β 1, which may play a role in the synovial membrane [45]. Many other ECM-fibroblast interactions are of potential relevance in the synovial membrane (Table 3) [46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61].

The most important receptor family binding and responding to ECM is formed by integrins, which are heterodimeric molecules comprising, to date, 16 alpha and 8 beta subunits. The β1 integrins bind collagens, laminins, entactin/nidogen, fibronectin, tenascin and vascular cell adhesion molecule-1, whereas β2 integrins are mainly expressed in blood leukocytes and perform a role in both immune inflammation, and in heterotypic interactions of fibroblasts with other cells. The αV integrins mediate adhesion to provisional matrix molecules, such as fibrinogen, fibronectin, vitronectin, thrombospondin and osteopontin. In addition to these three major subclasses, α6β4 integrin, as a component of hemidesmosomes, forms a receptor for laminin-5 and laminin-10. The αIIbβ3 and α4β7 integrins, as well as αEβ7 integrin, perform roles in platelet function and vascular adhesion, respectively [41]. Integrin subunitsα3, α4, α5, α6, αV and β1 are overexpressed in synovitis [48].Nonintegrin receptors, such as CD44, binding hyaluronan, and also other ligands (such as collagens I and VI), are of importance in this respect. CD44-hyaluronan interaction modulates the migration of inflammatory leukocytes into the extravascular compartment of the synovial membrane.
Table 3

Interactions between extracellular matrix (ECM) proteins and fibroblast-like synoviocytes (FLS)




Laminin (Ln)

Ln is synthesized in rat and human FLS, and is involved in FLS adhesion



FLS adhesion to Ln shows enhanced proliferative ability in response to PDGF



RA-FLS bind to Ln more strongly than normal FLS, with monoclonal antibodies to integrin α 3, α 6,



β 1 subunits partly blocking this adhesion


Fibronectin (Fn)

FLS plated on the substrate containing Fn show extensive focus formation, and enhanced adhesion



and proliferation


CS-1 Fn correlates with FLS proliferation



ED-A Fn is associated with activation of FLS



FLS adhering to Fn show higher proliferative ability in response to PDGF



Adhesion to Fn through integrin α 5β 1 downregulates the collagenase expression in human FLS



RA-FLS bind more strongly to Fn than normal FLS; anti-α 5, or β 1 monoclonal antibodies block the





Rabbit FLS cultured on the substrate containing Fn fragment show upregulated expression of



procollagenase and prostromelysin


Vitronectin (Vn)

FLS adhering to Vn shows higher proliferative ability in response to PDGF. Adhesion to Vn through



integrin α v downregulates collagenase expression in human FLS


Tenascin (Tn)

FLS synthesize Tn



RA-FLS bind more strongly to Tn than normal FLS; monoclonal antibodies to integrin β 1 block adhesion



Rabbit FLS cultured on Tn/Fn mixed substrate show increased expression of collagenase, stromelysin,



the 92 kDa gelatinase, and c-fos


Hyaluronan (HA)

Synthesized by FLS, degraded by macrophage-like lining cells



HA inhibits proliferation of FLS



Modulates MMP-1 gene expression of rabbit FLS when present on the substrate with Vn or Fn fragment



Involved in adhesion and growth of FLS


Collagen type I

FLS adhering to collagen type I show higher proliferative ability in response to PDGF. Adhesion to



collagen type I through integrin β 1 downregulates the collagenase expression in human FLS


Collagen type IV

Synthesized by FLS



RA-FLS bind more strongly to collagen type IV than normal FLS



monoclonal antibodies to integrin β 1 block adhesion



Degraded by MMP-2, MT-MMP



Degraded by matrilysin


CS-1, connecting sequence 1; ED-A, extra domain-A; MMP, matrix metalloproteinase; MT, membrane type; PDGF, platelet derived growth factor; RA, rheumatoid arthritis.

Cell-cell interactions

Direct cell-cell interactions are typical for epithelial cells, but direct cell-cell contacts have been considered rare in connective tissue. Connective tissue cells such as fibroblasts were thought to be regulated not only by soluble factors, but also by effects resulting from ECM-fibroblast interactions. However, time-lapse cinephotomicrography and light and electron microscopy have been used to show close physical apposition and adhesion between fibroblasts and other cells. This adhesion is not only a passive event, but can affect one or both of the interacting cells. Such events have been proven to be dependent on cell-cell contact by the lack of effect of cell culture supernatant (ie in the physical absence of one of the interacting cells). Similar conclusions have been drawn based on the inhibition of the observed effect upon use of physical barriers between the interacting cells (eg their separation by membranes). This abolishes cellular events dependent on cell-cell interaction. Many of these heterotypic interactions are dependent on the β2 (CD18) integrins, shown by the use of blocking antibodies. Adherens junctions have been reported between fibroblasts. Another relatively new and unexpected finding is that gap junctions are present in fibroblasts. Built up from transmembrane proteins, connexons, gap junctions allow the spread of small molecular second messagers like Ca2+ and cAMP from one cell to another. Transfection of fibroblasts with the `receptor for hyaluronic acid-mediated motility' regulates gap junctional intercellular communication and connexin-43 expression, affecting focal adhesion and cytoskeleton organization, with various secondary effects on motility, growth and transformation (Table 4) [62,63,64,65,66,67,68,69,70,71,72,73].
Table 4

Direct cell-cell interactions between fibroblasts and other cell types

Cell type




Direct transfer (of FITC-dextran, mannose BSA gold) from macrophages to fibroblasts



Neutrophil adhesion to fibroblasts is increased by PMA treatment of neutrophils and by IL-1α



or TNF-α treatment of fibroblasts


Fibroblasts provide directional guidance to adhering neutrophils



PAF and IL-8 enhance neutrophil adhesion to and motility of adhered neutrophils along



fibroblasts, respectively, in an integrin β2 dependent process



Fibroblasts synthesize IL-1α, IL-1β, IL-6 and ICE



Fibroblast mediated synthesis of collagen type I and type III is decreased



Activated eosinophils adhere to fibroblasts: this adhesion is inhibited with RGDS


Mast cell

Formation of mast pseudopods and their translocation to fibroblast surface



Mast cell stimulates fibroblast proliferation after cell-cell contact in an IL-4 dependent manner



Gap junctions between the mast cell and fibroblast are possible


Osteoblast-like cells

Osteoblast-like cells stimulate fibroblast proliferation (regulation of osteoprogenitor cell





BSA, bovine serum albumen; ICE, interleukin-1β -converting enzyme; IL, interleukin; FITC, fluorescein isothiocyanate; PAF, platelet-activating factor; PMA, phorbol myristate acetate; RGDS, arginyl-glycyl-aspartyl-serine; TNF, tumor necrosis factor.


It has been claimed that the rheumatoid arthritis synovial fibroblasts differ from their nonrheumatoid counterparts in terms of growth rate, life span, glycolytic metabolism, synthesis of hyaluronan and sulfated glycosaminoglycans, acid hydrolase activities, and metabolic and structural mitochondrial proteins [1]. The rheumatoid fibroblasts show a sustained and distinct morphology and pattern of gene activation [74,75], and might represent nonrheumatoid fibroblasts, but might also be phenotypically altered chondrocytes or bone marrow derived stem cells. These differences between the normal and the inflammatory synovium may be due to a selection pressure in the synovial mileau, where water- and lipid-soluble stimuli, cyclic loading, shear stress, ECM contacts and direct cell-cell contacts more or less permanently modulate the phenotype and function of fibroblast-like cells in the synovial lining, stroma and pannus.

Authors’ Affiliations

Institute of Biomedicine, Helsinki, Finland
Institute of Dentistry, University of Helsinki, Finland
Surgical Hospital, Helsinki, Finland


  1. Konttinen YT, Saari H, Santavirta S, Antti-Poika I, Sorsa T, Nykanen P, Kemppinen P: Synovial fibroblasts. Scand J Rheumatol. 1988, 76: 95-103.View ArticleGoogle Scholar
  2. Springer TA: Adhesion receptors of the immune system. Nature. 1990, 346: 425-434.PubMedView ArticleGoogle Scholar
  3. Callard RE, Gearing AJH: . The Cytokine Facts London: Academic Press. 1994Google Scholar
  4. Ohgoda O, Sakai A, Koga H, Kanai K, Miyazaki T, Niwano Y: Fibroblast-migration in a wound model of ascorbic acid-supplemented three-dimensional culture system: the effects of cytokines and malotilate, a new wound healing stimulant, on cell-migration. J Dermatol Sci. 1998, 17: 123-131.PubMedView ArticleGoogle Scholar
  5. Ware MF, Wells A, Lauffenburger DA: Epidermal growth factor alters fibroblast migration speed and directional persistence reciprocally and in a matrix-dependent manner. J Cell Sci. 1998, 111: 2423-2432.PubMedGoogle Scholar
  6. Yule KA, White SR: Migration of 3T3 and lung fibroblasts in response to calcitonin gene-related peptide and bombesin. Exp Lung Res. 1999, 25: 261-273.PubMedView ArticleGoogle Scholar
  7. Andresen JL, Ehlers N: Chemotaxis of human keratocytes is increased by platelet-derived growth factor-BB, epidermal growth factor, transforming growth factor-alpha, acidic fibroblast growth factor, insulin-like growth factor-I, and transforming growth factor-beta. Curr Eye Res. 1998, 17: 79-87.PubMedView ArticleGoogle Scholar
  8. Postlethwaite AE, Seyer JM, Kang AH: Chemotactic attraction of human fibroblasts to type I, II, and III collagens and collagen-derived peptides. Proc Natl Acad Sci USA. 1978, 75: 871-875.PubMedPubMed CentralView ArticleGoogle Scholar
  9. Dean JW, Blankenship JA: Migration of gingival fibroblasts on fibronectin and laminin. J Periodontol. 1997, 68: 750-757.PubMedView ArticleGoogle Scholar
  10. Senior RM, Griffin GL, Mecham RP, Wrenn DS, Prasad KU, Urry DW: Val-Gly-Val-Ala-Pro-Gly, a repeating peptide in elastin, is chemotactic for fibroblasts and monocytes. J Cell Biol. 1984, 99: 870-874.PubMedView ArticleGoogle Scholar
  11. Postlethwaite AE, Snyderman R, Kang AH: Generation of a fibroblast chemotactic factor in serum by activation of complement. J Clin Invest. 1979, 64: 1379-1385.PubMedPubMed CentralView ArticleGoogle Scholar
  12. Kondo H, Yonezawa Y, Ito H: Interferon-beta, an autocrine cytokine, suppresses human fetal skin fibroblast migration into a denuded area in a cell monolayer but is not involved in the age-related decline of cell migration. Mech Ageing Dev. 1996, 87: 141-153.PubMedView ArticleGoogle Scholar
  13. Adelmann-Grill BC, Hein R, Wach F, Krieg T: Inhibition of fibroblast chemotaxis by recombinant human interferon gamma and interferon alpha. J Cell Physiol. 1987, 130: 270-275.PubMedView ArticleGoogle Scholar
  14. Hein R, Mensing H, Muller PK, Braun-Falco O, Krieg T: Effect of vitamin A and its derivatives on collagen production and chemotactic response of fibroblasts. Br J Dermatol. 1984, 111: 37-44.PubMedView ArticleGoogle Scholar
  15. Mensing H, Czarnetzki BM: Generation and characterization of a neutrophil-derived inhibitor of fibroblast chemotaxis. Arch Dermatol Res. 1986, 278: 184-189.PubMedView ArticleGoogle Scholar
  16. Bitterman PB, Wewers MD, Rennard SI, Adelberg S, Crystal RG: Modulation of alveolar macrophage-driven fibroblast proliferation by alternative macrophage mediators. J Clin Invest. 1986, 77: 700-708.PubMedPubMed CentralView ArticleGoogle Scholar
  17. Basilico C, Moscatelli D: The FGF family of growth factors and oncogenes. Adv Cancer Res. 1992, 59: 115-165.PubMedView ArticleGoogle Scholar
  18. Brinckerhoff CE: Morphologic and mitogenic responses of rabbit synovial fibroblasts to transforming growth factor beta require transforming growth factor alpha or epidermal growth factor. Arthritis Rheum. 1983, 26: 1370-1379.PubMedView ArticleGoogle Scholar
  19. Denk PO, Knorr M: Effect of heparin on human corneal fibroblast proliferation in vitro with and without growth factor stimulation. Graefes Arch Clin Exp Ophthalmol. 1999, 237: 342-347. 10.1007/s004170050242.PubMedView ArticleGoogle Scholar
  20. Ludwig CU, Menke A, Adler G, Lutz MP: Fibroblasts stimulate acinar cell proliferation through IGF-I during regeneration from acute pancreatitis. Am J Phys. 1999, 276: 193-198.Google Scholar
  21. Kratz G, Lake M, Ljungstrom K, Forsberg G, Haegerstrand A, Gidlund M: Effect of recombinant IGF binding protein-1 on primary cultures of human keratinocytes and fibroblasts: selective enhancement of IGF-1 but not IGF-2-induced cell proliferation. Exp Cell Res. 1992, 202: 381-385.PubMedView ArticleGoogle Scholar
  22. Gitter BD, Koehneke EM: Retinoic acid potentiates interleukin-1-and fibroblast growth factor-induced human synovial fibroblast proliferation. Clin Immunol Immunopathol. 1991, 61: 191-120.PubMedView ArticleGoogle Scholar
  23. Haynes JH, Johnson DE, Mast BA, Diegelmann RF, Salzberg DA, Cohen IK, Krummel TM: Platelet-derived growth factor induces fetal wound fibrosis. J Pediatr Surg. 1994, 29: 1405-1408.PubMedView ArticleGoogle Scholar
  24. Jutley JK, Wood EJ, Cunliffe WJ: Influence of retinoic acid and TGF-beta on dermal fibroblast proliferation and collagen production in monolayer cultures and dermal equivalents. Matrix. 1993, 13: 235-241.PubMedView ArticleGoogle Scholar
  25. Yu F, Itoyama Y, Kira J, Fujihara K, Kobayashi T, Kitamoto T, Suzumura A, Yamamoto N, Nakajima Y, Goto I: TNF-beta produced by human T lymphotropic virus type I-infected cells influences the proliferation of human endothelial cells and fibroblasts. J Immunol. 1994, 152: 5930-5938.PubMedGoogle Scholar
  26. Hanemaaijer R, Sorsa T, Konttinen YT, Ding Y, Sutinen M, Visser H, van Hinsbergh VW, Helaakoski T, Kainulainen T, Ronka H, Tschesche H, Salo T: Matrix metalloproteinase-8 is expressed in rheumatoid fibroblasts and endothelial cells. J Biol Chem. 1997, 272: 31504-31509.PubMedView ArticleGoogle Scholar
  27. Deleuran BW, Chu CQ, Field M, Brennan FM, Katsikis P, Feldmann M, Maini RN: Localization of tumor necrosis factor receptors in the synovial tissue and cartilage-pannus junction in patients with rheumatoid arthritis. Implications for local actions of tumor necrosis factor alpha. Arthritis Rheum. 1992, 35: 1170-1178.PubMedView ArticleGoogle Scholar
  28. Gross SS, Wolin MS: Nitric oxide: pathophysiological mechanisms. Annu Rev Physiol. 1995, 57: 737-769.PubMedView ArticleGoogle Scholar
  29. Sakurai H, Kohsaka H, Liu MF, Higashiyama H, Hirata Y, Kanno K, Saito I, Miyas N: Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest. 1995, 96: 2357-2363.PubMedPubMed CentralView ArticleGoogle Scholar
  30. McInnes IB, Leung BP, Field M, Wei XQ, Huang FP, Sturrock RD, Kinninmonth A, Weidner J, Mumford R, Liew FY: Production of nitric oxide in the synovial membrane of rheumatoid and osteoarthritis patients. J Exp Med. 1996, 184: 1519-1524.PubMedView ArticleGoogle Scholar
  31. Nussler AK, Billiar TR: Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol. 1993, 54: 171-178.PubMedGoogle Scholar
  32. Borderie D, Hilliquin P, Hernvann A, Lemarechal H, Menkes CJ, Ekindjian OG: Apoptosis induced by nitric oxide is associated with nuclear p53 protein expression in cultured osteoarthritic synoviocytes. Osteoarthritis Cartilage. 1999, 7: 203-213.PubMedView ArticleGoogle Scholar
  33. Mitchell JA, Larkin S, Williams TJ: Cyclooxygenase-2: regulation and relevance in inflammation. Biochem Pharmacol. 1995, 50: 1535-1542.PubMedView ArticleGoogle Scholar
  34. Wu KK: Inducible cyclooxygenase and nitric oxide synthase. Adv Pharmacol. 1995, 33: 179-207.PubMedView ArticleGoogle Scholar
  35. DiBattista JA, Martel-Pelletier J, Fujimoto N, Obata K, Zafarullah M, Pelletier JP: Prostaglandins E2 and E1 inhibit cytokine-induced metalloprotease expression in human synovial fibroblasts. Mediation by cyclic-AMP signalling pathway. Lab Invest. 1994, 71: 270-278.PubMedGoogle Scholar
  36. Takahashi S, Inoue T, Higaki M, Mizushima Y: Cyclooxygenase inhibitors enhance the production of tissue inhibitor-1 of metalloproteinases (TIMP-1) and pro-matrix metalloproteinase 1 (proMMP-1) in human rheumatoid synovial fibroblasts. Inflamm Res. 1997, 46: 320-323. 10.1007/s000110050194.PubMedView ArticleGoogle Scholar
  37. Agro A, Langdon C, Smith F, Richards CD: Prostaglandin E2 enhances interleukin 8 (IL-8) and IL-6 but inhibits GMCSF production by IL-1 stimulated human synovial fibroblasts in vitro. J Rheumatol. 1996, 23: 862-868.PubMedGoogle Scholar
  38. Panchenko MV, Farber HW, Korn JH: Induction of heme oxygenase-1 by hypoxia and free radicals in human dermal fibroblasts. Am J Physiol Cell Physiol. 2000, 278: C92-C101.PubMedGoogle Scholar
  39. Maines MD: Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J. 1988, 2: 2557-2568.PubMedGoogle Scholar
  40. Melillo G, Taylor LS, Brooks A, Musso T, Cox GW, Varesio L: Functional requirement of the hypoxia-responsive element in the activation of the inducible nitric oxide synthase promoter by the iron chelator desferrioxamine. J Biol Chem. 1997, 272: 12236-12243.PubMedView ArticleGoogle Scholar
  41. Frisch SM, Vuori K, Ruoslahti E, Chan-Hui PY: Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol. 1996, 134: 793-799.PubMedView ArticleGoogle Scholar
  42. Shiozawa K, Shiozawa S, Shimizu S, Fujita T: Fibronectin on the surface of articular cartilage in rheumatoid arthritis. Arthritis Rheum. 1984, 27: 615-622.PubMedView ArticleGoogle Scholar
  43. Hino K, Shiozawa S, Kuroki Y, Ishikawa H, Shiozawa K, Sekiguchi K, Hirano H, Sakashita E, Miyashita K, Chihara K: EDA-containing fibronectin is synthesized from rheumatoid synovial fibroblast-like cells. Arthritis Rheum. 1995, 38: 678-683.PubMedView ArticleGoogle Scholar
  44. Müller-Ladner U, Elices MJ, Kriegsmann JB, Strahl D, Gay RE, Firestein GS, Gay S: Alternatively spliced CS-1 fibronectin isoform and its receptor VLA-4 in rheumatoid arthritis synovium. J Rheumatol. 1997, 24: 1873-1880.PubMedGoogle Scholar
  45. Konttinen YT, Li T-F, Mandelin J, Liljestrom M, Sorsa T, Santavirta S, Virtanen I: Increased expression of EMMPRIN in rheumatoid synovium. Arthritis Rheum. 2000, 43: 275-280.PubMedView ArticleGoogle Scholar
  46. Nozawa-Inoue K, Ajima H, Takagi R, Maeda T: Immunocytochemical demonstration of laminin in the synovial lining layer of the rat temporomandibular joint. Arch Oral Biol. 1999, 44: 531-534.PubMedView ArticleGoogle Scholar
  47. Sarkissian M, Lafyatis R: Integrin engagement regulates proliferation and collagenase expression of rheumatoid synovial fibroblasts. J Immunol. 1999, 162: 1772-1779.PubMedGoogle Scholar
  48. Rinaldi N, Schwarz-Eywill M, Weis D, Leppelmann-Jansen P, Lukoschek M, Keilholz U, Barth TF: Increased expression of integrin on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins. Ann Rheum Dis. 1997, 56: 45-51.PubMedPubMed CentralView ArticleGoogle Scholar
  49. Wolf J, Carsons S: Fibronectin mediates anchorage-dependent focus formation in cultured human synoviocytes. Semin Arthritis Rheum. 1992, 21: 387-392.PubMedView ArticleGoogle Scholar
  50. Carsons S, Wolf J: Interaction between synoviocytes and extra-cellular matrix in vitro. Ann Rheum Dis. 1995, 54: 413-416.PubMedPubMed CentralView ArticleGoogle Scholar
  51. Damsky C, Tremble P, Werb Z: Signal transduction via the fibronectin receptors: do integrins regulate matrix remodeling?. Matrix. 1992, 1: 184-191.PubMedGoogle Scholar
  52. McCachren SS, Lightner VA: Expression of human tenascin in synovitis and its regulation by interleukin-1. Arthritis Rheum . 1992, 35: 1185-1196.PubMedView ArticleGoogle Scholar
  53. Tremble P, Chiquet-Ehrismann R, Werb Z: The extracellular matrix ligands fibronectin and tenascin collaborate in regulating collagen gene expression in fibroblasts. Mol Biol Cell. 1994, 5: 439-453.PubMedPubMed CentralView ArticleGoogle Scholar
  54. Asari A, Kuriyama S, Kominami E, Uchiyama Y: Cytochemical localization of hyaluronic acid in human synovium with special reference to its possible process of degradation. Arch Histol Cytol. 1995, 58: 65-76.PubMedView ArticleGoogle Scholar
  55. Goldberg RL, Toole BP: Hyaluronate inhibition of cell proliferation. Arthritis Rheum. 1987, 30: 769-778.PubMedView ArticleGoogle Scholar
  56. Huttenlocher A, Werb Z, Tremble P, Huhtala P, Rosenberg L, Damsky CH: Decorin regulates collagenase gene expression in fibroblasts adhering to vitronectin. Matrix Biol. 1996, 15: 239-250.PubMedView ArticleGoogle Scholar
  57. Dodge GR, Boesler EW, Jimenez SA: Expression of the basement membrane heparin sulfate proteoglycan (perlecan) in human synovium and in cultured human synovial cells. Lab Invest. 1995, 73: 649-657.PubMedGoogle Scholar
  58. Schneider M, Voss B, Rauterberg J, Menke M, Pauly T, Michlke RK, Friemann J, Gerlach U: Basement membrane proteins in synovial membrane. Clin Rheumatol. 1994, 13: 90-97.PubMedView ArticleGoogle Scholar
  59. Okada Y, Morodomi T, Enghild JJ, Suzuki K, Yasui A, Nakanishi I, Salvesen G, Nagase H: Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts. Purification and activation of the precursor and enzymic properties. Eur J Biochem. 1990, 194: 721-730.PubMedView ArticleGoogle Scholar
  60. Seiki M: Membrane-type matrix metalloproteinases. APMIS . 1999, 107: 137-143.PubMedView ArticleGoogle Scholar
  61. Wilson CL, Matrisian LM: Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol. 1996, 28: 123-136.PubMedView ArticleGoogle Scholar
  62. Dean MF, Cooper JA, Stahl P: Cell contact and direct transfer between co-cultured macrophages and fibroblasts. J Leukoc Biol. 1988, 43: 539-546.PubMedGoogle Scholar
  63. Dean MF, Rodman J, Levy M, Stahl P: Contact formation and transfer of mannose BSA gold from macrophages to co-cultured fibroblasts. Exp Cell Res. 1991, 192: 536-542.PubMedView ArticleGoogle Scholar
  64. Shock A, Laurent GJ: Adhesive interactions between fibroblasts and polymorphonuclear neutrophils in vitro. Eur J Cell Biol. 1991, 54: 211-216.PubMedGoogle Scholar
  65. Behzad AR, Chu F, Walker DC: Fibroblasts are in a position to provide directional information to migrating neutrophils during pneumonia in rabbit lungs. Microvasc Res. 1996, 51: 303-316.PubMedView ArticleGoogle Scholar
  66. Burns AR, Simon SI, Kukielka GL, Rowen JL, Lu H, Mendoza LH, Brown ES, Entman ML, Smith CW: Chemotactic factors stimulate CD18-dependent canine neutrophil adherence and motility on lung fibroblasts. J Immunol. 1996, 156: 3389-3401.PubMedGoogle Scholar
  67. Murakami S, Hino E, Shimabukuro Y, Nozaki T, Kusumoto Y, Saho T, Hirano F, Hirano H, Okada H: Direct interaction between gingival fibroblasts and lymphoid cells induces inflammatory cytokine mRNA expression in gingival fibroblasts. J Dent Res. 1999, 78: 69-76.PubMedView ArticleGoogle Scholar
  68. Rezzonico R, Burger D, Dayer JM: Direct contact between T lymphocytes and human dermal fibroblasts or synoviocytes down-regulates types I and III collagen production via cell-associated cytokines. J Biol Chem. 1998, 273: 18720-18728.PubMedView ArticleGoogle Scholar
  69. Shock A, Rabe KF, Dent G, Chambers RC, Gray AJ, Chung KF, Barnes PJ, Laurent GJ: Eosinophils adhere to and stimulate replication of lung fibroblasts `in vitro'. Clin Exp Immunol . 1991, 86: 185-190.PubMedPubMed CentralView ArticleGoogle Scholar
  70. Greenberg G, Burnstock G: A novel cell-to-cell interaction between mast cells and other cell types. Exp Cell Res. 1983, 147: 1-13.PubMedView ArticleGoogle Scholar
  71. Trautmann A, Krohne G, Brocker EB, Klein CE: Human mast cells augment fibroblast proliferation by heterotypic cell-cell adhesion and action of IL-4. J Immunol. 1998, 160: 5053-5057.PubMedGoogle Scholar
  72. Oliani SM, Girol AP, Smith RL: Gap junctions between mast cells and fibroblasts in the developing avian eye. Acta Anat (Basel). 1995, 154: 267-271.View ArticleGoogle Scholar
  73. van der Plas A, Nijweide PJ: Cell-cell interactions in the osteogenic compartment of bone. Bone. 1988, 9: 107-111.PubMedView ArticleGoogle Scholar
  74. Ritchlin C, Dwyer E, Bucala R, Winchester R: Sustained and distinctive patterns of gene activation in synovial fibroblasts and whole synovial tissue obtained from inflammatory synovitis. Scand J Immunol. 1994, 40: 292-298.PubMedView ArticleGoogle Scholar
  75. Zvaifler NJ, Tsai V, Alsalameh S, von Kempis J, Firestein GS, Lotz M: Pannocytes: distinctive cells found in rheumatoid arthritis articular cartilage erosions. Am J Pathol. 1997, 150: 1125-1138.PubMedPubMed CentralGoogle Scholar


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