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Matricellular proteins in the heart: possible role during stress and remodeling

Mark W.M. Schellings, Yigal M. Pinto, Stephane Heymans
DOI: http://dx.doi.org/10.1016/j.cardiores.2004.06.006 24-31 First published online: 1 October 2004


Matricellular proteins are extracellular matrix proteins that modulate cell–matrix interactions and cell function, and do not seem to have a direct structural role. The family includes tenascin-C (TN-C), tenascin-X (TN-X), osteonectin, osteopontin, thrombospondin-1 (TSP1) and thrombospondin-2 (TSP2). Expression of matricellular proteins is high during embryogenesis, but almost absent during normal postnatal life. Interestingly, it re-appears in response to injury.

Left ventricular remodeling is a complicated process that occurs in the stressed heart, and is still not completely understood. Several members of the matricellular protein family, like tenascin-C, osteopontin, and osteonectin are up-regulated after cardiac injury. Therefore, this group of proteins may have crucial functions in the heart coping with stress. This review will focus on the expression, regulation and function of these matricellular proteins, and will discuss the crucial functions that these proteins might exert during remodeling of the stressed heart.

  • Glycoproteins
  • Matricellular proteins
  • Remodelling
  • Extracellular matrix
  • Matrix metalloproteinases

1. Introduction

A well-organized extracellular matrix is necessary to maintain strength and organization of cardiac tissue and is involved in communication between different cardiac cells. The last decade we have witnessed increasing interest in a group of ‘matrix’ proteins that modulate cell function but do not appear to have a direct structural role in the extracellular matrix of the heart [1]. These matrix proteins have been termed ‘matricellular’ proteins to highlight their role in modulating cell function.

The current review will focus on the biological role is matricellular proteins in the heart, in particular tenascin-C (TN-C), tenascin-X (TN-X), thrombospondin-1 (TSP1), thrombospondin-2 (TSP2), osteonectin (also known as SPARC or BM-40) and osteopontin (OPN).

A common property of matricellular proteins is their high expression during embryogenesis, which strongly decreases after birth, when expression becomes low to absent during normal adult life. Their expression re-appears at high levels during tumor growth and after tissue injury [1], indicating a role for these proteins in migration and proliferation of malignant and wound healing cells, and in remodeling of the extracellular matrix. Matricellular proteins may indeed regulate cellular function and matrix production by binding to their cellular receptors [1,2], and by modulating expression and activity of growth factors, cytokines, and proteinases [1]. A variety of knockout mice has been generated to study the role of these matricellular proteins. Surprisingly, all of the mouse models where these proteins have been deleted by gene targeting survive embryogenesis, suggesting redundancy of these proteins during embryonic development. These gene deficient mice only show a mild phenotype after birth, mainly consisting of some abnormalities of collagen formation, with resulting hyperflexibility of the skin as described in TN-X and TSP2 deficient mice [3,4]. Absence of matricellular proteins, however, resulted in striking abnormalities in wound healing and matrix remodeling after injury, clearly indicating that their re-expression after tissue injury is vital for normal tissue healing and remodeling [5–9].

The current review will first shortly describe the overall expression and function of each matricellular protein. Subsequently, it will focus more extensively on their expression and possible function in the heart.

2. Tenascin-C and tenascin-X

TN-C is the founding member of the extracellular matrix family of tenascins. Other family members are TN-R, TN-X, TN-Y and TN-W [10]. Since only TN-C and TN-X are described as modulators of cell adhesion, migration and growth, the current review will focus on these two tenascins.

TN-C is highly expressed during embryogenesis [11], whereas its expression is very low after birth. TN-C, however, reappears under pathological conditions, such as infection, vascular hypertension, myocardial infarction [12] or tumor formation [8,10]. TN-C possesses adhesive as well as counteradhesive activities, which depend on ECM and cell surface receptor binding. The counteradhesive effects of TN-C are termed “de-adhesion”, meaning the induction of a transition from a strong cell–ECM adherence to an intermediate cell–ECM adhesion, as described in some excellent reviews [2,8,10,13]. De-adhesion facilitates cell migration and tissue remodeling during wound healing.

TN-X is also widely expressed during embryogenesis, but, in contrast to TN-C, its expression persists after birth [14,15]. Until now, several functions of TN-X have been proposed. TN-X blocked invasion and metastasis of tumor cells [16,17], enhanced cell proliferation stimulated by VEGF family proteins [18,19], and modulated collagen fibrillogenesis [3]. TN-X gene inactivation in mice caused a syndrome of cutaneous hyperflexibility of the skin [3], mimicking the Ehlers–Danlos syndrome in human, which may also be caused by a mutation in the TN-X gene [20].

2.1. Tenascin-C and tenascin-X in the heart

TN-C was only detected in the chorda tendinae of papillary muscles of the normal adult myocardium [21]. However, TN-C reappeared under pathological conditions, including myocarditis [22], myocardial infarction [12,23], hibernating myocardium [24], and during dilated cardiomyopathy [25]. Its expression correlated with cardiac injury and inflammation, and level of TN-C expression has been proposed as a marker for the severity of viral myocarditis [22].

After myocardial infarction, TN-C appeared at the borderzone between the infarcted area and the intact myocardium where extensive remodeling occurred [12]. TN-C may exert a dual role in cardiac healing after myocardial infarction. TN-C may loosen cardiomyocytes from the matrix, thereby causing slippage of cardiomyocytes, and facilitating invasion of inflammatory cells and capillaries after myocardial infarction. It may also increase matrix production, thereby strengthening the cardiac matrix. Loosening of the cardiomyocytes from the matrix may occur by TN-C mediated de-adhesion. In addition, TN-C upregulates the transcription and activity of matrix metalloproteinases (MMPs) [26], promoting degradation of the extracellular matrix, and increasing the risk of cardiac dilatation and rupture after myocardial infarction [27–29]. Increased production of matrix, in contrast, may occur by TN-C mediated recruitment of myofibroblasts [12], which are the main cells involved in production of new collagen shortly after myocardial infarction [30]. In addition, elastic properties of TN-C [31] may also help to resist the increased mechanical loading to which the borderzone of the infarct is subjected. Whether TN-C reappearance after cardiac injury is beneficial or detrimental remains unclear, considering the paradoxical functions of TN-C in matrix remodeling. Whereas TN-C mediated de-adhesion [32] and increase in MMPs [26] might predispose to left ventricular dilatation, recruitment of myofibroblasts by TN-C and its elastic properties may strengthen the ventricle through accelerated fibrosis. The precise role of TN-C in matrix remodeling after cardiac injury or stress requires further investigation in mice lacking the TN-C gene.

In contrast to TN-C, TN-X was expressed in the heart during embryogenesis and adulthood, which implies a vital function for this protein in the development of the heart [33]. However, absence of TN-X in gene targeted mice did not result in an apparent cardiac phenotype, but resulted in reduction of collagen content in the skin with loss of tissue strength [3]. In addition, absence of TN-X resulted in increased activities of MMP-2 and MMP-9 [17]. Whether TN-X may regulate MMP activity, thereby affecting rupture or dilatation, or influence cardiac healing and remodeling after cardiac injury, requires further investigation.

3. Osteonectin

Osteonectin (also known as: Secreted Protein Acidic and Rich in Cysteine; SPARC or BM-40) is a 32-kDa glycoprotein that belongs to the family of matricellular proteins [34]. Expression of osteonectin is high during embryonic development, but very low during normal postnatal life, except in tissues undergoing continuous remodeling, such as the gut and bone [35,36]. However, osteonectin expression re-appeared after pathological insults, like myocardial infarction [37,38], and in malignant tumors [39], indicating a role in cell migration and matrix remodeling during pathological conditions.

Its implication in remodeling may occur through binding to TSP1, vitronectin, entactin, fibrillar collagens and collagen type IV [40], thereby regulating matrix organization. In addition, osteonectin is a substrate for transglutaminase, an enzyme that makes covalent cross-links between matrix proteins [41], mediating matrix assembly and cell–ECM interactions. Osteonectin expression also correlated with progression of different tumors [42–45]. Increase in MMP-2 activity by osteonectin, as shown in invasive human breast [46] and prostate cell lines [47], may in part explain increased invasiveness associated with increased expression of osteonectin.

Another important property of osteonectin is its counteradhesive activity. Addition of osteonectin to cultured endothelial cells caused dissociation of focal adhesion of endothelial cells to the matrix, resulting in modified cell shape with rounding of endothelial cells [48]. However, the exact mechanism of de-adhesion induced by osteonectin is incompletely understood [48].

Use of osteonectin deficient mice provided new insights in the function of osteonectin regarding cell function and matrix remodeling during wound healing, as already suggested by increased expression of osteonectin after injury. Indeed, osteonectin-null mice showed an altered cutaneous wound healing [5,6]. Together, these data indicate a crucial role of osteonectin in matrix assembly and reorganization, and in cell–matrix interaction during tissue injury and remodelling.

3.1. Osteonectin in the heart

Expression of osteonectin is abundant in the heart during fetal development [35,36]. In contrast, its expression in the heart is almost absent during adulthood [36], but re-appears in the heart after myocardial infarction [37,38] or adrenergic stimulation [49]. Absence of osteonectin in mice during embryogenesis resulted in smaller collagen fibrils that were more uniform in diameter [50], with curly tails and reduced tensile strength of the skin.

Whether absence of osteonectin may also alter formation of collagen in the normal heart is unknown. Expression of osteonectin mRNA strongly increased after myocardial infarction in the infarct zone of the rat heart, reaching a peak after 14 days [37,38]. Its expression paralleled the up-regulation of type I collagen mRNA after myocardial infarction, suggesting an implication of osteonectin in development of fibrosis during scar formation [37]. Osteonectin mRNA was also up-regulated in cardiac remodeling 3 and 7 days after β-adrenergic stimulation [49]. Osteonectin may modulate matrix remodeling and wound healing in the heart by different ways. First, osteonectin may alter activity of growth factors, including TGF-β, bFGF, PDGF and VEGF, which are involved in wound healing after cardiac injury [40,51,52]. Secondly, osteonectin may induce de-adhesion, involved in stimulating invasion of wound healing cells, but also facilitating myocyte slippage and cardiac dilatation. Finally, osteonectin may modulate angiogenesis [53–55], and might thereby influence infarct healing after myocardial injury. Whether osteonectin up-regulation after cardiac injury or during hemodynamic stress may be beneficial or detrimental for cardiac structure or function requires further investigation.

4. Osteopontin

The matricellular protein osteopontin (OPN) is to date the most extensively studied one regarding its role in the myocardium. OPN is highly expressed during embryonic development [56,57]. However, OPN expression is low in normal postnatal life except for the kidney, bone, and in epithelial linings of several tissues [58]. As described for other matricellular proteins, OPN expression clearly increased during pathological conditions, such as cancer [59], atherosclerosis [60], myocardial infarction [61], and focal stroke [62], indicating a role of OPN in matrix remodeling and cell–matrix interaction in diseased tissue. OPN is a multifunctional protein, not only expressed by bone cells, but also by inflammatory and wound healing cells, including macrophages, endothelial cells, smooth muscle cells and fibroblasts [63]. It mediates wound healing by regulating cell adhesion, migration and proliferation [7]. OPN has both pro- and anti-inflammatory effects [64] by regulating inflammatory cell adhesion [65,66], migration [65,66], cytokine release [67,68], and differentiation state [69]. As a pro-inflammatory agent, it appears to be crucial for the recruitment of macrophages to inflamed sites [66,70]. Inflammatory effects of OPN were clearly shown in mice lacking OPN. Lack of OPN also resulted in impaired wound healing after skin incisions with abnormal collagen formation and pronounced disorganization of the matrix [71]. In conclusion, OPN appears to be a key player in matrix remodelling and wound healing.

4.1. Osteopontin in the heart

Based on current literature, expression of OPN has never been demonstrated in the developing heart. OPN is expressed in cultured neonatal myocytes of rats, but its expression is absent in normal human myocardium [72]. OPN expression re-appears in response to injury. Indeed, increase of OPN was described after myocardial infarction, primarily in non-muscle cells in the interstitial space—probably infiltrating inflammatory cells [37,61,73], reaching its peak 2 to 3 days after the infarction. OPN also colocalized with interstitial fibroblasts in hypertrophic hearts of spontaneous hypertensive rats [74], rat hearts undergoing thermal injury [75], and in hypertrophic hearts of cardiomyopathic hamsters [76]. OPN expression coincided with the development of heart failure, and in situ hybridazation revealed primarily interstitial cells, probably fibroblasts, as the major source of OPN. In human hearts however, OPN expression was primarily present in myocytes of explanted hearts with ischemic, hypertrophic or idiopathic dilated cardiomyopathy [72]. In situ hybridisation indeed revealed cardiomyocytes as the dominant source of OPN synthesis and expression did not correlate with inflammatory cell invasion [72].

Clear genetic evidence for a crucial role of OPN in cardiac healing and remodeling was provided in OPN-null mice. Absence of OPN resulted in exaggerated LV dilatation, and decreased collagen deposition in both the infarcted and remote area of the heart after myocardial infarction [61]. Up-regulation of OPN after myocardial infarction thus protected against LV dilatation, implying a beneficial role for OPN in LV remodeling when coping with cardiac stress. Whether OPN-mediated decrease in MMP activity [77] may also be implicated in LV remodeling after myocardial injury has not been investigated. Taken together, OPN up-regulation may be necessary to maintain cardiac structure and function during cardiac injury or stress.

5. Thrombospondin 1 and 2

Thrombospondin (TSP) 1 and 2 belong to the thrombospondin family of extracellular glycoproteins, consisting of TSPs 1–5. TSP1 and TSP2 expression is high during embryogenesis, but spatial and temporal expression of TSP1 during embryogenesis differs from TSP2 [78–80]. During normal postnatal life, the expression of TSP1 and TSP2 is low. TSPs exert their function at the cell surface, where they bind to membrane proteins and cytokines, thereby regulating ECM structure and cellular phenotype. The three main molecular functions of TSP1 are activation of TGF-β, inhibition of angiogenesis and de-adhesion. First, TSP1 is a major activator of TGF-β1 in vivo [81]. Secondly, TSP1 was the first naturally occurring protein to be identified as an angiogenesis inhibitor [82]. TSP1 directly inhibits angiogenesis by induction of apoptosis and inhibition of migration of endothelial cells [83], and may indirectly inhibit angiogenesis by modulation of inflammatory cells and myofibroblasts [84].

Finally, TSP1 also induces de-adhesion in a variety of cells, including fibroblasts and endothelial cells [85], by stimulating the loss focal adhesions and actin stress fibers [85,86]. Despite its array of functions, the TSP1 null mice showed only a subtle phenotype, including mild spinal lordosis, acute and chronic inflammatory pulmonary infiltrates and an elevated number of white blood cells in the circulation [87].

As described for TSP1, TSP2 also inhibits angiogenesis and causes de-adhesion. Gene inactivation of TSP2 in mice indeed increased capillary density in various tissues at all stages of life [4]. Besides its anti-angiogenic function, TSP2 also inhibits focal adhesion in endothelial cells [88,89]. Absence of TSP2 in fibroblasts, however, caused defective attachment and spreading on matrix proteins, like fibronectin [4,90]. Increased levels of MMP2 activity in absence of TSP2 may in part explain the defect in fibroblast adhesion. The TSP2 null mice showed a more dramatic phenotype, as compared to TSP1 null mice, including a fragile skin associated with an abnormal collagen fibrillogenesis, increased vascularity in response to injury, increased cortical bone density, and a bleeding diathesis [4,79]. In conclusion, TSP1 and TSP2 are involved in wound healing by regulating growth factor signaling, angiogenesis and cellular adhesion.

5.1. Thrombospondin 1 and 2 in the heart

Both TSP1 and TSP2 are expressed in the heart during development, whereas their expression is low during normal postnatal life. However, TSP1 and TSP2 expression re-appears in response to injury, implicating that, if the same occurs in the heart, these proteins could be involved in the LV remodeling during/after pathological events in the heart, such as myocardial infarction, or chronic pressure overload.

TSP1 null mice may show an interesting phenotype after pathological insults in the heart. It is known that TSP1 null mice have a delayed wound healing associated with a reduced inflammatory response [87]. A delayed healing after, for instance, myocardial infarction may result in a reduced LV function.

TSP2 null mice display an abnormal collagen fibrillogenesis after birth and during cutaneous wound healing [9,87]. An important issue is whether collagen formation may be abnormal after cardiac injury or stress, resulting in abnormal cardiac remodeling and impaired cardiac function. Preliminary results indeed demonstrated that myocardial infarction in TSP2 null mice resulted in cardiac rupture 48 h after myocardial infarction in more than 90% of the null mice [91]. This striking phenotype suggests that TSP2 is essential to LV remodeling after myocardial infarction, and, may have an important role to maintain matrix integrity in the heart. Preliminary, yet unpublished data indicate that altered collagen formation may in part explain increased cardiac rupture after myocardial infarction. Whether increased inflammation in absence of TSP2 may predispose to weakening of the matrix, however, remains a vital question. Together, TSP2 appears to play a pivotal role in maintenance of cardiac integrity and structure.

6. Are matricellular proteins essential for the heart to cope with hemodynamic stress?

The matricellular proteins are a group of ECM binding proteins that exert their function by binding to matrix proteins, cell surface receptors or molecules such as cytokines. They do not have a direct structural role in the matrix, but modulate cell function and cell–matrix interactions [1]. Most of the matricellular proteins show an increased expression in the heart in response to injury or stress, which suggests a vital function of these proteins in wound healing and ventricular remodeling [12,37,61]. These matricellular proteins may alter cardiac remodeling by different ways. First, they may initiate de-adhesion between cardiomyocytes and the ECM, meaning the transformation from a strong cell–ECM adhesion to an intermediate cell–ECM adhesion, which allows cells to spread (Fig. 1) [2]. Secondly, matricellular proteins can decrease [17,77,92] or increase [26,46,47,93] (Fig. 1, Table 1) proteinases involved in cardiac remodeling and function in different cardiac diseases [27,94].

Fig. 1

A hypothetical scheme showing the possible role of the matricellular proteins in during LV remodeling of the heart. Expression of matricellular proteins increases in response to stress. Matricellular proteins induce de-adhesion (loosening of cell–matrix adherence), through loss of actin fibers and focal adhesion plaques. Thereby, matricellular proteins facilitate cell migration and cell infiltration. Matricellular proteins also regulate MMP activity involved in regulating matrix rearrangement during remodeling of the heart.

View this table:
Table 1

MMP activity regulation by matricellular proteins and characteristics of matricellular protein null mice

Matricellular proteinMMP activity regulationCharacteristics of the matricellular protein null miceReferences
Baseline matrix characterMatrix character after wound healingCardiac phenotype after MI
OsteopontinDecreases MMP-2 and -9No studiesSmall regular collagen fibrilsExaggerated LV dilatation[61,71,77]
OsteonectinIncreases MMP-2Immature collagen fibrilsSmall regular collagen fibrilsNo studies[5,46,47,50]
TSP1Increases MMP-2No changeNo changeNo studies[87,93]
TSP2Decreases MMP-2Abnormal collagen fibrilsLarge irregular collagen fibrilsCardiac rupture >90% within 3 days[9,87,90,91]
Tenascin-CIncreases MMP-9No studiesReduced fibronectin depositionNo studies[26,95]
Tenascin-XDecreases MMP-2 and -9Reduced collagen content in skinNo studiesNo studies[3,17]

Gene inactivation in mice in combination with cardiac disease models provides a unique tool to study the role of each individual matricellular protein in the stressed or injured heart. The null mice of the matricellular proteins all survived during embryogenesis, and only showed a mild phenotype. However, most of the null mice showed an altered response to wound healing, with changes in inflammation, angiogenesis, collagen fibrillogenesis or matrix deposition (Table 1).

Recently, the role of OPN and TSP2 after myocardial infarction has been examined in their respective null mice. Both the OPN and the TSP2 null mice showed a clear phenotype after MI. The OPN null mice had an exaggerated left ventricle dilatation [61], whereas >90% of the TSP2 null mice died after myocardial infarction due to cardiac rupture [91]. These data are striking and show that both OPN and TSP2 are necessary to maintain a normal cardiac structure and function after myocardial injury.

The multiple parallel features of the matricellular proteins suggest that, besides OPN and TSP2, also other family members may have crucial functions during ventricular remodeling of the stressed heart. More research is needed to clarify the roles of these matricellular proteins during ventricular remodeling in the injured heart.


This study was supported by a VIDI grant (016.036.346) from the Netherlands Organisation for Scientific Research (NWO) to Dr. Y.M. Pinto and a Dr. Dekkers grant of the Netherlands Heart Foundation (NHS, 2003T036) to Dr. S. Heymans.


  • Time for primary review 28 days


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