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(American Journal of Pathology. 2000;156:1489-1498.)
© 2000 American Society for Investigative Pathology

Review

Regulation of Tissue Injury Responses by the Exposure of Matricryptic Sites within Extracellular Matrix Molecules

George E. Davis^*, Kayla J. Bayless^*, Michael J. Davis and Gerald A. Meininger

From the Departments of Pathology and Laboratory Medicine^*
and Medical Physiology,
Texas A&M University Health Science Center, College Station, Texas

	Abstract

Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

 
Extracellular matrix (ECM) is known to provide signals controlling cell shape, migration, proliferation, differentiation, morphogenesis, and survival. Recent data shows that some of these signals are derived from biologically active cryptic sites within matrix molecules (matricryptic sites) that are revealed after structural or conformational alteration of these molecules. We propose the name, matricryptins, for enzymatic fragments of ECM containing exposed matricryptic sites. Mechanisms regulating the exposure of matricryptic sites within ECM molecules include the major mechanism of enzymatic breakdown as well as others including ECM protein multimerization, adsorption to other molecules, cell-mediated mechanical forces, and ECM denaturation. Such matrix alterations occur during or as a result of tissue injury, and thus, the appearance of matricryptic sites within an injury site may provide important new signals to regulate the repair process. Here, we review the data supporting this concept and provide insight into why the increased exposure of matricryptic sites may be an important regulatory step in tissue responses to injury.

	Introduction

Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

View larger version (33K): [in this window] [in a new window]   Figure 1. Schematic diagram illustrating how tissue injury leads to the generation of matricryptic sites and matricryptins which participate in the regulation of key aspects of tissue injury responses. FN, fibronectin; VN, vitronectin; FBG, fibrinogen; OPN, osteopontin; LM, laminin; TSP, thrombospondin.

	Matricryptic Sites and Matricryptins Regulate Cell and Tissue Responses

Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

An accumulating number of studies have suggested that matricryptic sites exist within ECM molecules and that these sites regulate biological phenomena such as ECM matrix assembly, formation of a wound repair scaffold, and receptor-mediated signal transduction which can induce a variety of important biological effects (Table 1 and Figure 1 ). Matricryptic sites and matricryptins have been reported within protein components of ECM as well as in glycosaminoglycans such as hyaluronic acid. Listed in Table 1 are ECM molecules with known matricryptic sites or which contain biologically active matricryptins. In addition, information is provided concerning the known activities and structure of individual matricryptic sites as well as mechanisms involved in their generation.

	Matricryptic Sites Are Revealed in Extracellular Matrix after Enzymatic Degradation, Heterotypic Binding to Other Molecules, Multimerization, Cell-Mediated Mechanical Forces, or Denaturation

Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

 
The mechanisms regulating the exposure of matricryptic sites may constitute an important step in the control of many biological processes (Figure 2 and Table 1 ). At least five mechanisms may play a role in generating these new sites and all share a common step that involves a change in ECM molecule structure or conformation. These changes can be induced in ECM molecules after 1) enzymatic degradation, 2) heterotypic binding to other molecules (adsorption), 3) multimerization (ie, self-assembly), 4) cell-mediated mechanical force, and 5) denaturation.

View larger version (23K): [in this window] [in a new window]   Figure 2. Mechanisms for the generation of matricryptic sites during tissue injury responses. Individual ECM proteins and known mechanisms for the generation of matricryptic sites are indicated.

In addition, matricryptic sites are revealed during ECM self-assembly or multimerization which has been observed with fibrinogen, vitronectin, and fibronectin.^{10,26-33,40,49,67} As many recent studies have indicated, ECM protein multimerization is a major mechanism regulating ECM assembly.¹⁰ In some cases, matricryptic sites may catalyze the multimerization process to stimulate the deposition of insoluble ECM.^29,49 For example, the addition of a recombinant 14-kd fibronectin fragment to intact fibronectin induces multimerization of fibronectin through a self-assembly mechanism involving covalent disulfide cross-links.²⁹ The disulfide-exchange reaction that participates in this multimerization event^10,29 has recently been attributed to an additional matricryptic site (ie, a Cys-X-X-Cys motif) in fibronectin which possesses disulfide isomerase activity.³³ A further example of these concepts is that monoclonal antibodies, which bind only to surface-adsorbed fibrinogen and not to soluble fibrinogen, were found to inhibit fibrin polymerization indicating that matricryptic sites are exposed and directly contribute to fibrin multimerization.⁴⁹ An important extension of these findings is that ECM multimerization increases matrix valency (perhaps by increasing the exposure of matricryptic sites) which then enhances cell-matrix interactions.^29,68

Enzymatic degradation of ECM and ECM protein denaturation are additional mechanisms that reveal matricryptic sites. Conformational changes in ECM secondary to denaturation are known to occur after proteolysis, oxidant damage, and thermal injury.^69-77 Cell types that are particularly efficient in inducing ECM denaturation during acute and chronic injury include leukocytes such as neutrophils and monocytes/macrophages (see below) and malignant tumor cells.^70,73,78,79 An excellent model of ECM denaturation is the well-described unfolding of triple helical collagen molecules that occurs after cleavage of triple-helical collagen by collagenases such as MMP-1 and MMP-8.^69,78,80 The triple helix of cleaved collagen molecules then undergoes thermal melting at 37°C. Thermal denaturation of intact collagen molecules similarly unfolds the triple helix at temperatures greater than 42°C,⁶⁹ a phenomenon that occurs in vivo after thermal injury to the skin.^76,77 Also, the unfolding of collagen renders its individual chains susceptible to broad spectrum proteases that can create biologically active collagen fragments (see below).⁶⁹

Leukocytes, such as neutrophils and macrophages, cause ECM denaturation by the action of secreted proteases (eg, elastase, collagenases, gelatinases) and oxidants.^73,78 Interestingly, neutrophils and monocytes express the integrins, Mß2 (Mac-1), Xß2 (p150,95), and 4ß1, which can interact with conformationally modified or denatured proteins.^81-84 Although the nature of the Mac-1, p150,95, and 4ß1 binding sites within denatured proteins remains unknown, the majority of proteins seem to possess them. Thus, leukocyte-derived ECM degrading agents may create leukocyte-integrin binding sites in their surrounding ECM. The ability of leukocytes to denature and degrade ECM could allow them to migrate into essentially any tissue site and may facilitate their ability to phagocytose diverse tissue or matrix debris. In related studies, we have recently found that the leukocyte integrins, 4ß1, Mß2, Xß2, and LRIß3, are all capable of binding osteopontin⁸⁵ (Bayless et al, unpublished observations), an Arg-Gly-Asp (RGD)-containing protein that is induced during injury and which is secreted in substantial amounts by macrophages. This may indicate a special role for osteopontin in leukocyte functions such as migration, tissue recruitment, and phagocytosis. Thus, osteopontin, an ECM protein known to be markedly induced during tissue injury, contains multiple integrin-binding sites (and perhaps matricryptic sites)^17,59,85 capable of regulating leukocyte and other cellular behaviors during wound repair responses.

	Matricryptic Sites Bind Integrins and Regulate Extracellular Matrix Assembly

Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

 
Recent data suggests that heterotypic binding, multimerization, or adsorption of ECM molecules can promote the exposure of matricryptic sites with affinity for integrins. The RGD integrin- and cell-binding site of vitronectin has recently been shown to be cryptic, in that it is not exposed in plasma vitronectin unless it adsorbs to surfaces or multimerizes.⁴⁰ This property may allow the RGD site of vitronectin to be exposed only when it is needed (ie, after increases in vascular permeability and binding of vitronectin into the ECM of injured tissues). A related and interesting question is whether the RGD sites within soluble plasma fibronectin are cryptic. A number of studies suggest that this is the case because monoclonal antibodies, which bind near the RGD site, bind weakly to fibronectin in solution but strongly bind after its adsorption.³⁴ Also, the 120-kd RGD-containing and cell-binding domain fragment of fibronectin can induce monocyte chemotaxis whereas the intact protein does not.³⁷ Structural analysis shows that the RGD site is present in a flexible loop which seems to be sensitive to cell-mediated mechanical forces.³⁵ In contrast to the above studies, this structural analysis suggested that appropriate forces applied to fibronectin molecules may actually decrease the accessibility of the RGD site to integrin binding. The above data together suggests that the RGD sites are present within a flexible domain that could be regulated (perhaps in a reversible manner) to expose or hide the sites depending on the biological situation. Other types of molecular interactions involving fibronectin heterotypic or self-assembly binding events may induce the exposure of its RGD sites (like those described for adsorption above) such as when fibronectin covalently cross-links into fibrin matrices, binds heparan sulfate proteoglycans, binds denatured collagen, or polymerizes during fibronectin matrix assembly.^{26-30,32,34-36} During this latter event, cells bind secreted fibronectin and exert tension on these molecules. This tension reveals matricryptic sites which promote fibronectin-fibronectin binding and assembly of a fibronectin matrix.^26,27 Experiments using a fibronectin-green fluorescent protein chimera have demonstrated that cell-bound fibronectin fibrils exhibit elasticity in response to changes in cell movement and shape.²⁸ These studies support the concept that cell-mediated mechanical forces can generate and perhaps regulate the exposure of matricryptic sites in ECM to effect ECM assembly and subsequent cellular responses. It is also well known that cell-mediated mechanical forces on ECM can regulate complex processes such as cellular morphogenesis²⁵ and some of these effects might be mediated by matricryptic sites.

	Matricryptic RGD Sequences in Collagens and the Probable Importance of RGD as a Wound Signal

Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

 
After the seminal discovery of the RGD cell-binding sequence in fibronectin and vitronectin,^86,87 it was recognized that collagens have multiple copies of this sequence. However, it became clear that cell attachment to native collagen substrates did not appear to involve RGD. Anti-integrin antibodies and RGD peptides which block the function of RGD-binding integrins failed to interfere with cell binding to native collagen substrates.^20,41 In contrast, other investigators showed that cell attachment to denatured collagen was RGD-dependent.^20,21,41 Davis²⁰ originally proposed that the exposure of RGD sites, which occurs during the transition from native to denatured collagen, might constitute a wound signal for cells. Furthermore, the vß3 integrin was shown to bind strongly to denatured collagen and minimally to native collagen in affinity chromatography experiments suggesting that the RGD sites in native collagen are cryptic.²⁰ In addition, the 2ß1 integrin which binds native collagen showed minimal binding to denatured collagen.^20,88 These results suggested the possibility that cells might use this information as part of a wound recognition system. Considerable recent work has provided support for this idea. For example, melanoma tumor cells are unable to proliferate and form a tumor without the vß3 integrin which is a receptor for denatured collagen.²¹ Matrix metalloprotease (MMP)-1-treated collagen was also shown to bind melanoma cell vß3.²¹ Furthermore, during normal bone resorption by osteoclasts, it was shown that denatured collagen and vß3 were present at cell matrix contact sites, whereas in adjacent sites, native collagen was present.⁸⁹ These data provide direct evidence for the potential importance of integrin-denatured collagen interactions in biologically important phenomena. Local collagen denaturation can result in the generation of matricryptic RGD signals delivered to cells through the vß3 integrin and may potentially eliminate or alter signals delivered through 2ß1 or a recently described native collagen-binding tyrosine kinase receptor.^5,6 A recent article reports that denatured type I collagen fragments induce focal contact disassembly in vascular smooth muscle cells in a manner that is not dependent on RGD sequences and that may involve 2ß1.⁴⁶ The above data supports the concept that collagen-derived matricryptic sites include RGD as well as non-RGD sites. Also, a recent report shows that cells are able to bend collagen fibrils⁹⁰ raising the possibility that cell-mediated mechanical forces exerted on collagen fibrils, like those mentioned above concerning cell-fibronectin interactions, might generate collagen-derived matricryptic sites.

	RGD Sites May Be a Fundamental Matricryptic Signal

Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

 
Many studies throughout the years suggest that RGD sites may represent a fundamental matricryptic signal within ECM proteins. A very important unanswered question concerns the normal density of RGD integrin-binding sites in noninjured tissues. We speculate that very few exposed RGD sites exist in normal tissue and that after tissue injury, a marked increase in the density of RGD sites will occur. Thus, RGD sequences may be an important mediator in tissue repair responses along with other mediators that regulate inflammatory or wound repair phenomena. The potential sources of this RGD signal include: 1) plasma-derived proteins, fibronectin, vitronectin, and fibrinogen; 2) alteration of pre-existing ECM proteins such as collagens; and 3) proteins synthesized in the wound site such as osteopontin, fibronectin, and tenascin. The abundance of collagens, and the fact that most collagens contain multiple RGD sequences (ie, 7- type I, 11- type IV, 11- type VI), strongly suggests that these proteins may constitute a biologically significant source of RGD sequences for cellular injury responses.

An important question is whether the exposure of RGD sites within tissue injury sites is required for appropriate responses of cells to initiate and propagate the wound-repair response program. A related consideration is whether RGD sites are necessary for malignant tumor growth and progression because the tumor microenvironment is reminiscent of wounds with a prominent provisional ECM containing fibrin and other RGD-containing proteins such as fibronectin and osteopontin.^16,91 Major cellular responses within wounds include proliferation, migration, phagocytosis, as well as differentiation and apoptosis.⁹² All of these responses are known to be regulated by RGD sequences and by RGD-binding integrins, such as vß3.⁹³ To illustrate this point further, one can consider the conditions used to propagate cells in tissue culture which mimic a wound environment. Two major proteins from serum that are critical to cell adhesion during growth in tissue culture are vitronectin and fibronectin,^86,87,93 both RGD-containing ECM proteins. Also, certain cell types such as endothelial cells proliferate more readily when the substrate is first coated with denatured collagen,⁹⁴ a protein containing multiple RGD sites. Denatured collagen substrates also strongly adsorb serum-derived fibronectin as well as fibronectin secreted from cells.⁴⁴ Intriguingly, heparin is also typically added to endothelial cells to enhance proliferation.⁹⁵ Thus, three components of a putative wound scaffold matrix are present (denatured collagen, fibronectin, heparin) to optimize endothelial cell growth (see later on). It would seem that optimal tissue-culture conditions include RGD-containing ECM substrates. What remains unclear is whether RGD signals are actually required for the growth of adherent normal or transformed cells. We speculate that the recruitment of RGD-containing proteins from plasma, the exposure of cryptic RGD sites from existing ECM, and the synthesis of RGD containing ECM proteins within wound sites provides evidence for an RGD signal requirement for appropriate cellular responses during tissue injury in vivo.

Other studies demonstrate the importance of RGD-mediated signaling in microvascular responses such as arteriolar vasomotor activity and the regulation of angiogenesis.^17,22,96-98 The vß3 integrin expressed on vascular smooth muscle cells was shown to regulate arteriolar vasodilation in response to RGD peptides^22,98 and this receptor is markedly induced on endothelial cells during angiogenesis.^96,99 Reagents which interfere with vß3 function can inhibit angiogenesis and induce vessel regression through an apoptotic mechanism.⁹⁷ In addition, vß3 has been reported to directly interact with MMP-2 on the cell surface to modulate both adhesive and proteolytic function.¹⁰⁰ One interesting aspect of this finding is that both vß3 (through RGD sites) and MMP-2 (through its fibronectin-like domain) have direct binding affinity for denatured collagen. This affinity may facilitate the interaction between vß3 and MMP-2 on the cell surface. Also, MMP-2 is a potent enzyme that degrades denatured collagens^70,100 and MMP-2, like other enzymes, should be capable of generating biologically active RGD-containing fragments from denatured collagen degradation. Such interactions may play an important role in the control of proteolytic balance which is a critical regulator of tissue morphogenesis and regression as well as tumorigenesis.^{2,70,79,101,102}

	Matricryptins Induce Signals, Alter Cell Behavior, and Alter Microvascular Responses

Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

 
Many studies throughout the years have strongly implicated the role of ECM breakdown in the generation of new biological signals. Enzymes that are either known to generate such fragments or which may participate in their generation include MMPs, serine proteases (ie, plasmin and neutrophil elastase), and enzymes that degrade glycosaminoglycans (ie, hyaluronidase and heparinase).^70-73,78 Here, we have proposed the name, matricryptins, to describe these biologically active fragments of ECM. Matricryptins are derived from molecular domains that are cryptic and enzymatic breakdown is required to expose the new biologically relevant activity. A series of biological activities can now be attributed to matricryptins such as effects on cell proliferation, vascular permeability, cell migration, arteriolar vasoreactivity, stimulation and inhibition of angiogenesis, ECM assembly, and focal contact stability (Table 1) .

Recent work from our laboratories²² has shown that proteolytic fragments of denatured collagen type I induce arteriolar vasodilation in a manner identical to that of synthetic RGD peptides (Figure 3) . In both cases, this vasodilatory response involved the vß3 integrin expressed by the arteriolar vascular smooth muscle. Blocking antibodies directed to vß3 were shown to inhibit these responses. Increased blood flow to injured tissues is a well-known consequence of tissue injury and may in part be controlled by this RGD matricryptin-mediated mechanism. Further studies using patch-clamp recordings have shown that soluble RGD peptides, when added to isolated vascular smooth muscle cells, decrease Ca²⁺ current through L-type Ca²⁺ channels.⁹⁸ This decreased Ca²⁺ current, which lowers intracellular Ca²⁺, is known to induce a vasodilatory response which is consistent with our results showing RGD peptide-induced vasodilation of intact arterioles.^22,103 Interestingly, this decreased Ca²⁺ current occurred equally well in vascular smooth muscle cells when the RGD signal was supplied in either a soluble or insoluble manner.⁹⁸ A previous study revealed an vß3 integrin signaling response to soluble ligands in endothelial cells.¹⁰⁴ In contrast, the 5ß1 integrin was found to increase Ca²⁺ current through L-type channels in vascular smooth muscle cells, but it could only signal when its ligands were presented in an insoluble form.⁹⁸ These data suggest that vß3 may possess a special ability among the integrin family of receptors to signal when ligands are presented in a soluble form. This property may allow this receptor to serve as a wound or RGD sensor to detect RGD locally or after diffusion from distant sites which could be an important component in a wound recognition and response system.

View larger version (22K): [in this window] [in a new window]   Figure 3. Generation of RGD-containing matricryptic sites and matricryptins from collagen type I regulates arteriolar vasomotor activity.

	Matricryptic Sites May Participate in the Formation of a Wound Repair Scaffold

Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

	Summary

Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

 
In summary, it is clear that matricryptic sites and matricryptins represent an important class of biological information that is revealed to cells during tissue injury responses. One of the most significant matricryptic sites is the RGD sequence, which appears to be a cryptic site in many, if not all, ECM proteins that possess the sequence. This sequence seems to play a special role in microvascular signaling by regulating arteriolar vasoactivity as well as angiogenic responses. The RGD sequence also appears to play a fundamental role in cell phenomena critical to the repair of injured tissue such as cell proliferation, migration, survival, morphogenesis, and phagocytosis. In addition to RGD sites, many recent studies have identified new non-RGD matricryptic sites that are currently being molecularly characterized. A wide variety of biological activities can now be attributed to these matricryptic sites and include effects on cell proliferation, migration, ECM matrix assembly, development of a wound repair scaffold, arteriolar vasoreactivity, focal adhesion stability, and morphogenesis. Thus, the regulated exposure of matricryptic sites represents a fundamental step during tissue repair responses and acts in concert with other mediators to control these events.

	Footnotes

 
Address reprint requests to George E. Davis, M.D., Ph.D., Department of Pathology and Laboratory Medicine, Texas A&M University Health Science Center, 208 Reynolds Medical Building, College Station, TX 77843-1114. E-mail: gedavis{at}tamu.edu

Supported by National Institutes of Health Grants HL 59373, HL 59971 (to G. E. D.), HL 55050 (to G. A. M.), and HL 46502 (to M. J. D.).

Accepted for publication January 13, 2000.

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Top Abstract Introduction Matricryptic Sites and... Matricryptic Sites Are Revealed... Matricryptic Sites Bind... Matricryptic RGD Sequences in... RGD Sites May Be... Matricryptins Induce Signals,... Matricryptic Sites May... Summary References

 

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