Three-Dimensional Contact with Type I Collagen Mediates Tyrosine Phosphorylation in Primary Human Fibroblasts

Roeckel, Dagmar; Krieg, Thomas

doi:10.1006/excr.1994.1056

Cited by 36 publications

(15 citation statements)

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“…Integrins convey information about the extracellular environment by serving as both a direct physical link between the ECM and actin cytoskeleton via the proteins, talin, and vincullin, and by functioning as signal transduction molecules to stimulate tyrosine phosphorylation cascades linked to MAPK and other pathways (45)(46)(47). Recently, Takeuchi and co-workers (48) provided compelling evidence for the involvement of focal adhesion kinase and MAPK in AA/collagen-dependent induction of alkaline phosphatase, an osteoblast differentiation marker.…”

Section: Discussionmentioning

confidence: 99%

Role of the α2-Integrin in Osteoblast-specific Gene Expression and Activation of the Osf2 Transcription Factor

Xiao

Wang

Benson

et al. 1998

Journal of Biological Chemistry

344

292

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Extracellular matrix molecules such as type I collagen are required for the adhesion, migration, proliferation, and differentiation of a number of cell types including osteoblasts. Matrix components often affect cell function by interacting with members of the integrin family of cell surface receptors. Previous work showed that collagen matrix synthesis, induced by addition of ascorbic acid to cells, precedes and is essential for the expression of osteoblast markers and induction of the osteocalcin promoter in murine MC3T3-E1 cells. This later response requires OSE2, the promoter element recognized by Osf2 (also called Cbfa1/AML3/PEBP2␣A), a recently identified osteoblast-specific transcription factor. Osteoblasts express several integrins including ␣2␤1 which is a major receptor for type I collagen. This paper examines the role of the ␣ 2 -integrin subunit in osteocalcin promoter activation and osteoblast differentiation. Disruption of ␣ 2 -integrin-ECM interactions with a blocking antibody or DGEA peptide containing the cell-binding domain of type I collagen blocked activation of the mouse osteocalcin gene 2 promoter by ascorbic acid as well as induction of endogenous osteocalcin mRNA and mineralization. Furthermore, anti-␣ 2 -integrin blocking antibody or peptide reduced ascorbic aciddependent binding of Osf2 to OSE2 without affecting levels of transcription factor mRNA. Time course studies revealed that ascorbic acid-dependent binding of Osf2 to OSE2 preceded increases in osteocalcin and bone sialoprotein expression and this increase in Osf2 binding was not accompanied by comparable changes in levels of transcription factor mRNA or protein. Taken together, these studies demonstrate that an ␣ 2 -integrincollagen interaction is required for activation of Osf2 and induction of osteoblast-specific gene expression. Furthermore, matrix signals may regulate Osf2 through a post-translational pathway or via an accessory factor.As a cell primarily devoted to matrix production, the osteoblast must have the ability to monitor the composition of the extracellular matrix (ECM) 1 it is secreting as well as adapt matrix composition to the changing mechanical needs of bone. Consistent with the concept that there is a dialogue between the osteoblast and its ECM, osteoblast precursors must secrete a collagenous matrix before they will differentiate. Inhibition of collagen synthesis by growing cells in the absence of ascorbic acid (AA) or through the use of specific inhibitors totally blocks osteoblast differentiation (1-6). In vivo, both bone formation and osteoblast differentiation, as assessed by expression of osteocalcin (OCN) and alkaline phosphatase mRNAs, are also severely reduced in vitamin C-deficient animals (7, 8). Thus, the ECM is an important, but poorly understood regulator of the osteoblast differentiation pathway.Integrins are the principle mediators of the molecular dialogue between a cell and its ECM environment (for reviews, see Refs 9 and 10). These transmembrane receptors convey information from the ECM to ...

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Section: Discussionmentioning

confidence: 99%

Role of the α2-Integrin in Osteoblast-specific Gene Expression and Activation of the Osf2 Transcription Factor

Xiao

Wang

Benson

et al. 1998

Journal of Biological Chemistry

344

292

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“…Previous observations have shown that seeding fibroblasts in collagen gel results in tyrosine phosphorylation of a 125-kDa protein corresponding to FAK (43) and that down-regulation of TGF-␤ receptor by collagen contact is dependent on the activity of FAK (54). In addition, activation of fibroblast and keratinocyte MMP-1 expression by three-and two-dimensional collagen, respectively, is dependent on tyrosine kinase activity (37,55).…”

Section: Fig 6-continuedmentioning

confidence: 98%

“…Accordingly, tyrosine phosphorylation has been shown to be involved in the signal transduction triggered by contact of fibroblasts to three-dimensional collagen (43) and it has been shown that contraction of collagen gel by fibroblasts requires protein-tyrosine phosphorylation (44). To elucidate the signaling mechanisms mediating the collagen-de- pendent induction of MMP-13 expression, we first added two different tyrosine kinase inhibitors to fibroblasts before seeding them in collagen gel.…”

Section: Induction Of Mmp-13 Expression In Fibroblasts Cultured In Comentioning

confidence: 99%

Induction of Collagenase-3 (MMP-13) Expression in Human Skin Fibroblasts by Three-dimensional Collagen Is Mediated by p38 Mitogen-activated Protein Kinase

Ravanti

Heino

López-Otı́n

et al. 1999

Journal of Biological Chemistry

267

218

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Collagenase-3 (matrix metalloproteinase-13, MMP-13) is a recently identified human MMP with an exceptionally wide substrate specificity and restricted tissue-specific expression. Here we show that MMP-13 expression is induced in normal human skin fibroblasts cultured within three-dimensional collagen gel resulting in production and proteolytic activation of MMP-13. Induction of MMP-13 mRNAs by collagen gel was potently inhibited by blocking antibodies against ␣ 1 and ␣ 2 integrin subunits and augmented by activating antibody against ␤ 1 integrin subunit, indicating that both ␣ 1 ␤ 1 and ␣ 2 ␤ 1 integrins mediate the MMP-13-inducing cellular signal generated by three-dimensional collagen. Collagen-related induction of MMP-13 expression was dependent on tyrosine kinase activity, as it was abolished by treatment of fibroblasts with tyrosine kinase inhibitors genistein and herbimycin A. Contact of fibroblasts to three-dimensional collagen resulted in simultaneous activation of mitogen-activated protein kinases (MAPKs) in three distinct subgroups: extracellular signal-regulated kinase (ERK)1 and ERK2, Jun N-terminal kinase/ stress-activated protein kinase, and p38. Induction of MMP-13 expression was inhibited by treatment of fibroblasts with a specific p38 inhibitor, SB 203580, whereas blocking the ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by PD 98059, a selective inhibitor of MEK1,2 activation potently augmented MMP-13 expression. Furthermore, specific activation of ERK1,2 pathway by 12-O-tetradecanoylphorbol-13-acetate markedly suppressed MMP-13 expression in dermal fibroblasts in collagen gel. These results show that collagen-dependent induction of MMP-13 in dermal fibroblasts requires p38 activity, and is inhibited by activation of ERK1,2. Therefore, the balance between the activity of ERK1,2 and p38 MAPK pathways appears to be crucial in regulation of MMP-13 expression in dermal fibroblasts, suggesting that p38 MAPK may serve as a target for selective inhibition of collagen degradation, e.g. in chronic dermal ulcers. Controlled degradation of extracellular matrix (ECM)1 is essential in physiologic situations involving connective tissue remodeling, such as tissue morphogenesis, angiogenesis, and tissue repair. On the other hand, excessive breakdown of connective tissue plays an important role in the pathogenesis of, e.g., rheumatoid arthritis, osteoarthritis, atherosclerosis, periodontitis, autoimmune blistering disorders of skin, and dermal photoaging, as well as in invasion and metastasis of tumor cells (see Refs. 1 and 2). Matrix metalloproteinases (MMPs) are a family of structurally related zinc-dependent endopeptidases collectively capable of degrading essentially all ECM components, and they apparently play an important role in ECM remodeling in the physiologic and pathologic situations mentioned above. At present, human MMP gene family contains 16 members, which can be divided into subgroups of collagenases, gelatinases, stromelysins, membrane-type MMPs, and novel MMPs based on their structure and substrate speci...

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“…Several years ago, we proposed a general model for ECM regulation of osteoblast differentiation in which the matrix was viewed as interacting with the cell surface through specific integrins to initiate intracellular signaling pathways leading to osteoblast-specific gene expression (Franceschi, 1992). Integrins are the principal mediators of the molecular dialogue between a cell and its ECM environment and are crucial to processes such as tissue morphogenesis, wound healing, and cell migration and attachment (for reviews, see Clark and Brugge, 1995;Gumbiner, 1996 (Roeckel and Krieg, 1994;Sudbeck et al, 1994;Lin et al, 1997).…”

Section: Extracellular Matrix Regulation Of Osteoblast-specific Gene mentioning

confidence: 99%

The Developmental Control of Osteoblast-Specific Gene Expression: Role of Specific Transcription Factors and the Extracellular Matrix Environment

Franceschi

1999

Critical Reviews in Oral Biology & Medicine

252

174

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Bone formation is a carefully controlled developmental process involving morphogen-mediated patterning signals that define areas of initial mesenchyme condensation followed by induction of cell-specific differentiation programs to produce chondrocytes and osteoblasts. Positional information is conveyed via gradients of molecules, such as Sonic Hedgehog that are released from cells within a particular morphogenic field together with region-specific patterns of hox gene expression. These, in turn, regulate the localized production of bone morphogenetic proteins and related molecules which initiate chondrocyte-and osteoblast-specific differentiation programs. Differentiation requires the initial commitment of mesenchymal stem cells to a given lineage, followed by induction of tissue-specific patterns of gene expression. Considerable information about the control of osteoblast-specific gene expression has come from analysis of the promoter regions of genes encoding proteins like osteocalcin that are selectively expressed in bone. Both general and tissue-specific transcription factors control this promoter. Osf2/Cbfal, the first osteoblast-specific transcription factor to be identified, is expressed early in the osteoblast lineage and interacts with specific DNA sequences in the osteocalcin promoter essential for its selective expression in osteoblasts. The OSF2/CBFAI gene is necessary for the development of mineralized tissues, and its mutation causes the human disease, cleidocranial dysplasia. Committed osteoprogenitor cells already expressing Osf2/Cbfa 1 must synthesize a collagenous ECM before they will differentiate. A cell:ECM interaction mediated by integrin-type cell-surface receptors is essential for the induction of osteocalcin and other osteoblast-related proteins. This interaction stimulates the binding of Osf2/Cbfa 1 to the osteocalcin promoter through an as-yet-undefined mechanism.

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Three-Dimensional Contact with Type I Collagen Mediates Tyrosine Phosphorylation in Primary Human Fibroblasts

Cited by 36 publications

References 0 publications

Role of the α2-Integrin in Osteoblast-specific Gene Expression and Activation of the Osf2 Transcription Factor

Role of the α2-Integrin in Osteoblast-specific Gene Expression and Activation of the Osf2 Transcription Factor

Induction of Collagenase-3 (MMP-13) Expression in Human Skin Fibroblasts by Three-dimensional Collagen Is Mediated by p38 Mitogen-activated Protein Kinase

The Developmental Control of Osteoblast-Specific Gene Expression: Role of Specific Transcription Factors and the Extracellular Matrix Environment

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