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1 Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON, Canada M5S 3G5;
2 CIHR Group in Matrix Dynamics, Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ON, Canada M5S 3E2
* corresponding author, ringuet{at}zoo.utoronto.ca
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ABSTRACT |
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 TOP ABSTRACT (1) INTRODUCTION(2) MODULAR ORGANIZATION AND...(3) CALCIUM-DEPENDENT BINDING OF...(4) RELATIONSHIP OF SPARC...(5) LESSONS LEARNED FROM...(6) COLLAGEN ASSEMBLY AND...(7) POTENTIAL ROLE OF...REFERENCES |
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-chains are assembled into triple-helical procollagen molecules. This unique assembly of the procollagen molecules is guided by several endoplasmic reticulum resident molecular chaperones, including HSP47, which dissociates from procollagen molecules prior to their transport from the endoplasmic reticulum into the cis-Golgi network. SPARC, an evolutionarily conserved collagen-binding glycoprotein, which is frequently co-expressed with collagen in rapidly remodeling tissues, binds to the triple-helical region of procollagen molecules. Analysis of data from genome projects indicates that specific amino acids and sequences in SPARC that are critical for collagen binding are evolutionarily conserved in organisms ranging from nematodes to mammals. Studies of invertebrates, which do not encode HSP47, indicate that SPARC expression is required for the deposition of collagen IV in basal lamina during embryonic development. In mammals, defects in collagen deposition have been observed in normal and wound-healing tissues in the absence of SPARC expression. Based on these and other observations, we propose that intracellular SPARC acts as a collagen molecular chaperone in the endoplasmic reticulum, and that in higher organisms, SPARC acts in concert with HSP47 to ensure that only correctly folded procollagen molecules exit the endoplasmic reticulum. In contrast to HSP47, SPARC is transported from the endoplasmic reticulum through the Golgi network and into secretory vesicles for exocytosis at the plasma membrane. Hence, SPARC may also play a role in regulating post-endoplasmic reticulum events that promote collagen fibrillogenesis.
KEY WORDS: SPARC • collagen • molecular chaperone • fibrillogenesis • HSP47
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(1) INTRODUCTION |
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Several of the SCPP family members play a critical role in tetrapod tissue mineralization. These include the enamel matrix proteins (EMLs), amelogenin (AMEL), ameloblastin (AMBN), and enamelin (ENAM) that are secreted by ameloblasts and form the enamel matrix, which begins to mineralize during the early stages of tooth development. The EMLs are subsequently degraded by proteases secreted by the ameloblasts during the maturation phase, allowing for growth of the hydroxyapatite crystals and the formation of highly mineralized mature enamel that is essentially devoid of proteins. Notably, phylogenetic analysis of EMLs indicates that ENAM, derived from SPARCL1, gave rise, via gene duplication, to the sister genes AMEL and AMBN (Kawasaki and Weiss, 2006; Sire et al., 2006). Another subset of SCPPs, produced by odontoblasts and osteoblasts, is associated with the mineralization of dentin and bone. These include dentin sialophosphoprotein (DSPP), dentin matrix acidic phosphoprotein 1 (DMP1), bone sialoprotein/integrin-binding sialoprotein (BSP/IBSP), osteopontin/secreted phosphoprotein 1 (OPN/SPP1), and matrix extracellular phosphoprotein (MEPE). Based on common characteristics and chromosomal location, these SCPPs are collectively referred to as the SIBLING (Small Integrin-binding Ligand, N-linked Glycoproteins) family (Fisher et al., 2001). Phylogenetic analyses indicate that SIBLINGs, like the EMLs, are derived from SPARCL1 by gene duplication. Interestingly, SPARCL1 is part of the SIBLING gene cluster in both human and mouse SIBLINGs, whereas SPARC is located on a separate chromosome, consistent with SIBLINGs originating from SPARCL1, and SPARCL1 originating from SPARC (Kawasaki and Weiss, 2006).
SPARC also belongs to a group of regulatory ECM macromolecules, known as matricellular proteins, that modulate cell-matrix interactions and cell function, but do not seem to have a direct structural role in the matrix (Brekken and Sage, 2001; Bornstein and Sage, 2002). This family also includes tenascin-C, tenascin-X, osteopontin, and thrombospondin-1 and -2. Expression of matricellular proteins is generally high during embryogenesis and markedly reduced or absent during normal post-natal life. However, they re-appear in response to inflammation, tissue injury and remodeling, and in tumor growth and metastasis (Bornstein and Sage, 2002). Previous studies have shown that the high expression of SPARC in developing tissues—such as the notochord, somites, and the embryonic skeleton (Mason et al., 1986; Holland et al., 1987)—is retained in rapidly remodeling connective tissues, including bone and periodontal tissues (Salonen et al., 1990). Interestingly, immunohistochemical staining of periodontal tissues of mice shows that SPARC is prominently associated with the cells, rather than in the matrix, in both the soft and mineralized tissues (Fig. 1
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Despite differences in pattern formation, developmental strategies, and tissue organization, recent studies indicate that the basic molecular mechanisms governing the development of multicellular organisms are often highly conserved. This is particularly true of collagens, which show a striking evolutionary conservation of structure and function in organisms ranging from Porifera, the most basal animal lineage, to mammals. While direct evidence of molecular interactions between SPARC and different types of collagens is derived primarily from mammalian studies, analyses of genetic and molecular data indicate that these interactions also occur in invertebrates (Maurer et al., 1997). We believe that an ancient and conserved function of SPARC is to serve as a chaperone for promoting collagen folding, secretion, and maturation into complex supramolecular assemblies that define the biophysical properties of diverse connective tissues and basement membranes/basal lamina.
This review begins with an examination of the evidence for the evolutionary conservation of SPARC, followed by an analysis of the relationship of SPARC with collagens of basement membranes of invertebrates, and both basal lamina and fibril-forming collagens in vertebrates. We then critically assess evidence indicating that SPARC has an evolutionarily conserved role in the secretion of collagens and their extracellular assembly.
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(2) MODULAR ORGANIZATION AND BIOCHEMICAL PROPERTIES OF SPARC |
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) (Hohenester et al., 1996; Sage, 1997; Martinek et al., 2002), which are described below with human SPARC as a vertebrate prototype.
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,3)]. Since the concentration of free Ca+2 in the extracellular matrix is estimated to range from 0.1 mM to 1.2 mM (Maurer and Hohenester, 1997), it is predicted that Domain I will bind to several Ca+2 ions, whether SPARC is associated with soft or mineralized tissues. In ancient organisms that do not form mineralized tissues, such as Caenorhabditis elegans, Domain I contains 8 lysine residues, and the number of acidic residues is reduced by approximately 35% relative to mammalian SPARC (Maurer et al., 1997). Despite the decreased acidity, C. elegans SPARC still has a significant affinity for Ca+2 ions (Maurer et al., 1997). While Domain I of Drosophila melanogaster has an amino acid sequence composition more complex than that of C. elegans, the glutamic and aspartic acid-rich segments are also interrupted by lysine residues, which are likely to decrease its affinity for Ca+2 ions. Notably, as evident in the immunostaining shown in Fig. 1, much lower levels of SPARC are found associated with the mineralized matrix of bone and dentine in rodents, which indicates that there are also species differences in the calcium-binding properties of the amino-terminal region of mammalian SPARC (Zung et al., 1986). Studies in vitro also indicate that Domain I mimics several calcium-dependent and calcium-independent activities associated with native SPARC, such as the inhibition of cell proliferation and chemotaxis, decrease in fibronectin and thrombospondin-1 expression, and the enhancement of plasminogen activator inhibitor-1 expression (Lane et al., 1992). Hence, Domain I appears to have multiple functions, some of which have likely been retained during evolution.
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Domain III: a Calcium-binding EF-hand-like Module Found in Animal Phyla ranging from Cnidarians to Vertebrates
The collagen-binding C-terminal half of SPARC (Domain III, amino acids 138–286) is the most evolutionarily conserved region. This -helical-rich domain contains 2 high-affinity Ca2+-binding EF-hands (EF-1 and EF-2) (Hohenester et al., 1997), which are designated as an "EC domain" (Extracellular Calcium Domain) to distinguish them from cytosolic EF-hands of regulatory proteins, such as calmodulin (Sasaki et al., 1998). Binding of Ca2+ to the EF-hands increases the content of -helical secondary structure in SPARC, which is dependent on cooperative interactions between the EF-hands and the FS-domain. EFs are low-capacity, high-affinity Ca+2-binding motifs that mediate diverse intracellular processes, such as the conversion of ion-based Ca+2 signals into biochemical responses. In resting cells with an intracellular free Ca+2 concentration of 0.1 µM, the EF-hands of regulatory proteins, such as calmodulin (Kd ~ 1 µM), are in the unbound state. As the intracellular Ca2+ concentration increases to 10 µM, binding of Ca+2 to the EF hands occurs, inducing a conformational change that, in turn, regulates the activity of intracellular targets, such as second-messenger kinases and signal transduction receptors. In the Ca2+-rich environment of tissue fluids and connective tissues, the EF-hands of SPARC would be saturated with Ca2+, promoting structural changes that, in many other intracellular EF proteins, are required for functional activity. Thus, it is conceivable that the Ca2+-induced structural changes induced in SPARC are related to functional activities that have yet to be identified.
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(3) CALCIUM-DEPENDENT BINDING OF SPARC TO COLLAGENS |
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(4) RELATIONSHIP OF SPARC TO BASEMENT MEMBRANE TYPE IV COLLAGEN IN INVERTEBRATES |
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chains are encoded by 6 genes, the most abundant chain being the [1(IV)]2 2(IV) heterotrimer (Hudson et al., 1993). In contrast to fibrillar collagens, type IV molecules are not processed upon secretion; they retain their N- and C-propeptide domains, and assemble into polygonal sheets. Features of type IV collagen include a carboxy-terminal non-collagenous domain (NC-1), a 350-nm-long triple-helical domain, and an amino-terminal 7S domain. Ca2+-dependent self-assembly occurs by tetramerization of the 7S domain via antiparallel interactions, NC1 domain dimerization, and lateral associations (Risteli et al., 1980; Timpl et al., 1981; Yurchenco and Furthmayr, 1984). Lateral associations are facilitated by the presence of several short non-collagenous sequences, interrupting the triple-helical domain and introducing flexibility. A major function of collagen IV is to provide tensile strength to basement membranes throughout development. For example, in mice, collagen IV expression by the primitive endoderm coincides with that of laminin-1 at day 4.5–5 post-coitus (p.c.) (Li et al., 2002). However, in contrast to laminin-1 null embryos, which show a distinct phenotype by day 6 p.c., lethality is not observed until embryonic day 10.5–11.5 p.c. in type IV collagen mutants (Poschl et al., 2004). A plausible explanation for the absence of a collagen IV phenotype shortly after its zygotic expression begins is that a major function of collagen IV is to provide embryonic basement membranes with tensile strength, which becomes critical with the onset of significant muscle contractions by mid-embryogenesis (Yurchenco et al., 2004). However, other factors may also be involved. Thus, like other components of basement membranes, collagen IV, via interactions with cell-surface integrin receptors, also plays a direct role in promoting cell-matrix cell attachment, epithelial morphogenesis and polarity, cell migration, and signal transduction.
Protein sequences derived from expressed sequence tags and genomic data indicate that FS and SPARC-like EC domains are structural motifs that appeared very early during the evolution of multicellular animals. For example, a SMOC (Secreted Modular Calcium Binding Protein)-like protein containing FS and EC SPARC-like domains, albeit separated by a thyroglobulin type-1 (Tg-1) motif, is expressed by the starlet sea anemone Nematostella vectensis, which also codes for a testican-like glycoprotein containing a single SPARC-like EC module preceding a Tg-1 module. However, since there are few identical amino acids between the SPARC-like EC domain of cnidarian SMOC-like and testican-like proteins and the collagen-binding domain of SPARC, it is unlikely that these cnidarian proteins bind to collagens (Kawasaki and Weiss, 2006). Therefore, it remains to be established whether a bona fide ortholog of SPARC is present within the cnidarian genome. One possibility is that cnidarians do not express SPARC, and that SPARC was generated later by the excision of the Tg-1 domain from duplication of an ancestral SMOC-like gene.
Molecular and genetic evidence implicating an association between SPARC and basement membranes, where SPARC may interact with collagen IV in relatively simple metazoans, has been derived from studies of C. elegans and D. melanogaster (Fitzgerald and Schwarzbauer, 1998; Martinek et al., 2002). Immunohistochemical studies indicate that SPARC is co-localized with basement membranes along the body-wall muscle cells in C. elegans. In adult nematodes, SPARC is concentrated at the boundaries between muscle cells and is localized in basement membranes surrounding the sex muscles, which terminate at the vulva, the distal tip cells in the gonads, and the pharynx. Reduction of SPARC by RNA interference leads to embryonic and larval lethality (Fitzgerald and Schwarzbauer, 1998). Clues to the underlying cause of lethality come from mutational studies indicating that a sequence of 5 amino acids within the FS-EC domains of SPARC is essential for collagen-binding (Fig. 4). While these 5 amino acids are 100% conserved in evolutionarily distant vertebrates, analysis of invertebrate sequences revealed single-residue substitutions. An N156Q substitution is found in the closely related nematodes C. elegans and C. briggsae, and an M245L substitution in the closely related flies D. melanogaster and D. pseudoabscura. In both cases, these relatively minor amino acid changes should not affect the structure and function of this domain significantly. Consistent with this presumption is a study demonstrating that the affinity of C. elegans SPARC for collagen (Kd = 0.5–2.2 µM) is similar to human SPARC (Sasaki et al., 1998). Hence, it is likely that the localization of SPARC to basement membranes in C. elegans is partly dependent on interactions with collagen IV. Drawing a parallel to our studies with D. melanogaster (Martinek et al., unpublished observations), the absence of SPARC could in turn affect the deposition and/or stability of collagen IV during C. elegans embryonic development.
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That SPARC interacts with collagen IV in Drosophila is supported by the high sequence conservation of dSPARC within the collagen-binding domain (Fig. 4). As with C. elegans, there is only one amino acid change between dSPARC and vertebrate SPARC in these two regions. An intriguing observation is that, while the deposition of collagen IV in basement membranes appears to require SPARC expression, in the absence of collagen IV, SPARC protein expression by macrophages is not detected by immunohistochemistry, even though significant levels of SPARC mRNA are detected by in situ hybridization. Hence, at least with respect to Drosophila, the translation and perhaps stability of SPARC in the endoplasmic reticulum may be affected by the absence of collagen IV, indicative of a mutual dependence of these proteins for their secretion.
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(5) LESSONS LEARNED FROM VERTEBRATE STUDIES |
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Clues to the biological significance of the SPARC-collagen interactions in vertebrates are primarily derived from histological analyses of SPARC-null mice, which indicate that the absence of SPARC affects the supramolecular assembly of both network and fibrillar collagens. While SPARC-null mice appear normal, cataract formation is detected two months after birth (Gilmour et al., 1998; Norose et al., 1998). Ultrastructural examination of the cataract lens capsule has revealed cellular extensions emigrating from the lens epithelium into the overlying lens capsule (Norose et al., 2000). From histological analyses, the collagen IV and laminin networks of the lens capsule were altered, indicating that SPARC may play a role in the supramolecular assembly, maturation, and stability of these two major capsule components. Further evidence that SPARC is required for the deposition of normal levels of collagen IV is derived from data demonstrating that mammary tumors grown in the fat pads of SPARC-null mice show decreased collagen IV deposition in surrounding reactive stroma compared with wild-type mice. Collagen IV deposition is partially restored by the transplanting of bone marrow derived from wild-type mice into SPARC-null mice that were lethally irradiated to destroy host bone marrow (Sangaletti et al., 2003). Whether the collagen IV was derived from bone marrow cells or induced by the expression of SPARC remains to be resolved. It is conceivable that leukocyte-derived SPARC may stimulate TGF-ß signaling, which in turn could lead to increased collagen deposition.
While appearing normal, the skin of SPARC-null mice is significantly more fragile than in wild-type mice. Ultrastructural analysis of dermal tissues has revealed that the type I collagen fibrils are smaller and more uniform in size than in wild-type animals, resulting in skin with decreased tensile strength (Bradshaw et al., 2003). Consistent with an interaction between collagens and SPARC, an embryonic lethal mutation in the mouse 1(I) collagen gene (Mov-13) that prevents type I collagen secretion also causes the retention of SPARC within the endoplasmic reticulum and its subsequent absence from the ECM (Iruela-Arispe et al., 1996). Restoration of type I collagen expression in cell culture leads to the secretion of SPARC and its association with the reconstituted collagen fibrils. While it is hypothesized that the presence of other members of the SPARC family functionally compensate for the lack of SPARC expression (Brekken and Sage, 2001), leading to mild defects in SPARC-null mice, the formation of native collagen networks and fibrils appears to be dependent on direct interactions with SPARC. Thus, even though the closely related SPARC paralog SC1 also binds to collagens and has counter-adhesive effects on cell-matrix adhesion (Hambrock et al., 2003), the supra-molecular organization of fibrillar collagen in SC1-SPARC double-knockout mice is similar to that of SPARC-null mice (Barker et al., 2005b). Hence, SPARC appears to have the more dominant effect on collagen biosynthesis, secretion, and maturation in vertebrates, despite the presence of other family members.
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(6) COLLAGEN ASSEMBLY AND FOLDING IN THE ENDOPLASMIC RETICULUM: DOES SPARC SERVE AS A COLLAGEN CHAPERONE? |
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The folding, assembly, and processing of collagens from cells via the secretory pathway is dependent on several molecular chaperones and folding proteins found in the endoplasmic reticulum, such as Heat-shock protein 47 (HSP47), BiP/(glucose-related protein-78), prolyl-4-hydroxylase (P4H), protein disulfide isomerase (PDI), and peptidylproline cis-trans isomerase. HSP47 is a 47-kDa collagen-specific chaperone, also known as colligin (Hebert et al., 1999), that binds preferentially to the collagenous triple-helical domains of collagen molecules (Nagata, 2003). In HSP47-null mice, the secretion of fibril-forming collagens and collagen IV and their integration into an extracellular matrix are severely compromised, leading to embryonic lethality at day 10.5 to 11.5 p.c (Poschl et al., 2004). Immunoelectron microscopy has revealed that basement membranes are rarely observed, and that collagen IV accumulates within the dilated endoplasmic reticulum of mutant cells, leading to the activation of stress responses critical for cellular homeostasis and the prevention of apoptosis. In HSP47-null embryos, massive apoptotic cell death occurs at day 10.5 p.c., just prior to the death of the embryo. Collagen molecules that bypass the endoplasmic reticulum-quality control in HSP47-null fibroblasts and embryonic stem (ES) cells show increased sensitivity to protease degradation, indicative of improperly folded procollagen molecules (Marutani et al., 2004). Studies indicate that PDI and P4H bind to collagen chains as they enter the endoplasmic reticulum, ensuring proper folding and trimerization of the nascent -chains that proceed from the C-terminus. Both PDI and P4H are released from procollagen once triple-helix formation begins, setting the stage for HSP47 to associate with the nascent triple-helix domain (Nagata, 2003). The current concept is that HSP47 acts as a molecular chaperone by stabilizing the triple helix of collagen molecules, preventing their premature unfolding and the lateral aggregation of procollagen molecules in the endoplasmic reticulum (Nagata, 1996; Tasab et al., 2000; Matsuoka et al., 2004). Following the release of HSP47 from procollagen in acidic cis-Golgi compartments, the procollagen molecules associate in register to form characteristic segment-long spacing (SLS) aggregates, which appear in the secretory vesicles.
We propose that, in vertebrates, SPARC has chaperone activities similar to those of HSP47 and acts in concert with HSP47 to stabilize collagen triple helices prior to the translocation of collagen molecules from the endoplasmic reticulum (Fig. 5). Similar to HSP47, SPARC has been shown to bind to the triple-helical collagenous domain of procollagen and collagen in vitro (Fig. 5). Interestingly, SPARC binds to a domain of procollagen I with a high net-positive charge (amino acids 600–800) located one-third the distance from the C-terminus (Veis and George, 1994; Wang et al., 2005). Hence, electrostatic interactions are likely to make a major contribution to the preferential association of SPARC within this region of collagen I. This region of collagen also contains the collagenase-sensitive site and serves as a binding site for several ligands, including 2ß1 integrin (Xu et al., 2000) and fibronectin (Ingham et al., 2002). Hence, the binding of SPARC to this region may influence the activity of receptors and other ECM molecules known to have important roles in regulating collagen, secretion, fibrillogenesis, and remodeling.
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) (Tung et al., 1985). SPARC and collagen I are also co-expressed at high levels in the reactive stroma of tumors (Brown et al., 1999) and in the post-inflammatory stages of wound repair and scar tissue formation (Reed et al., 1993). Notably, SPARC and collagen expression are both up-regulated with fibronectin by the pro-fibrotic cytokine TGF-ß (Wrana et al., 1988). In organisms such as Drosophila, which do not express HSP47 or fibrillar collagens, SPARC may serve as the principle collagen IV chaperone. However, in vertebrates where SPARC and HSP47 are co-expressed in many tissues—such as the notochord, somites, soft and mineralized connective tissues—a supportive chaperone role is envisioned for SPARC in the endoplasmic reticulum. This may partly explain why, in SPARC-null mice, which express normal levels of HSP47, dermal collagens appear smaller and more uniform in size. It is also possible that the differences between normal and SPARC-null mice reflect the potential of a more prominent chaperone role for SPARC following the release of HSP47 from collagens and their exit from the endoplasmic reticulum.
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(7) POTENTIAL ROLE OF SPARC IN COLLAGEN SECRETION AND MATURATION |
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). In this regard, it will be important to demonstrate the association of SPARC with type IV and fibrillar procollagens in the secretary pathway, which will require dual immunogold labeling studies using differently sized gold particles for the interacting proteins. While a great deal remains to be understood about transport through the Golgi network and Golgi-to-plasma-membrane transport and sorting, it is interesting to note that vesicle transport from the endoplasmic reticulum to the Golgi and from the Golgi to the plasma membrane is microtubule-dependent. Our studies with Xenopus laevis indicate that, during embryonic development, SPARC is abundant in tubulin-rich structures, such as the neural tube and the surface cilia of embryonic skin (Damjanovski et al., 1994; Huynh et al., 2000). By immunogold electron microscopy, we demonstrated that SPARC is associated with the 9 + 2 microtubule arrays of the cilia (Huynh et al., 2000, 2004), an interaction confirmed by co-immunoprecipitation and pull-down assays (Huynh et al., 2004). The removal of N- and C-propeptides from fibrillar procollagen by procollagen propeptidases in plasma-membrane-enclosed extracellular compartments triggers the self-assembly of collagen molecules. Several factors have been shown to play a critical role in regulating the rate of formation and size of the fibrils, including selective cleavage of the collagen propeptide domains, co-assembly with other collagen types, and interactions with other extracellular matrix molecules, such as the small proteoglycans decorin, fibromodulin, lumican, and the glycoprotein fibronectin. Tissue culture studies indicate that fibronectin assembly at the cell surface is a necessary prerequisite for proper collagen assembly (Robinson et al., 2004). This is of particular interest in light of a recent demonstration that SPARC binds to integrin-linked kinase (ILK) by phage display (Barker et al., 2005a), a multifunctional serine-threonine kinase that interacts with the cytoplasmic domain of the ß1 integrin and functions as an adaptor molecule, modulating focal adhesion and multiple signaling pathways, including the TGF-ß pathway. Fibronectin-induced activation of ILK is enhanced by interaction of ILK with SPARC. Activated ILK promotes actinomyosin contractions through the phosphorylation and inactivation of MLCP (myosin light-chain phosphatase), with the resultant cell-mediated contractile forces promoting the unfolding of fibronectin dimers and their subsequent assembly into fibrils. Interestingly, ILK inactivation is observed only in cells expressing SPARC and is not rescued in SPARC-null fibroblasts by exogenously added SPARC (Barker et al., 2005a), consistent with an intracellular association between SPARC and ILK. Thus, SPARC may also indirectly promote collagen fibrillogenesis by functioning in the assembly of fibronectin provisional matrices. This may partly account for the larger and less uniform sizes of collagen fibrils observed in wild-type mice relative to SPARC-null mice. Another possibility is that the N-terminal calcium-binding domain of SPARC forms a calcium-dependent interaction with the glycosaminoglycan side-chain of decorin. Studies indicate that decorin binds to procollagens prior to fibril assembly. In the absence of decorin, larger abnormal collagen fibrils are formed. Hence, it is conceivable that SPARC could modulate the regulatory effects of decorin on fibrillogenesis.
While a collagen-specific chaperone role for SPARC is an intriguing possibility, it is important to note that, in the absence of collagen IV in Drosophila, the levels of SPARC immunostaining in hemocytes are decreased dramatically (Martinek et al., 2002), suggestive of a more complex relationship. Moreover, it is also possible that when collagen IV is not properly assembled extracellularly into a stable network, it is more susceptible to rapid degradation by matrix-remodeling proteases. However, the secretion of SPARC by non-macrophage cells does not rescue collagen IV deposition in basement membranes, indicating that intracellular interactions between SPARC and collagen IV are required for collagen IV deposition.
The chaperone activity proposed for SPARC shares a degree of similarity to the 67-kDa elastin-binding protein, a molecular chaperone that binds to tropoelastin in secretory vesicles, preventing coacervation of tropoelastin inside cells (Hinek et al., 2000). The 67-kDa elastin-binding protein remains bound to tropoelastin throughout the secretory pathway, and is released only upon contact with fibrillin-rich microfibrils, which act as scaffolds for assembly of tropoelastin into highly stable elastic fiber. Hence, like SPARC, the chaperone activity of the 67-kDa elastin-binding protein is not restricted to intracellular events. Recently, a chaperone-like activity for SPARC has been demonstrated in vitro with a thermal aggregation assay, with the chaperone target protein alcohol dehydrogenase as a substrate. Moreover, SPARC-B-crystallin double-knockout mice show precocious lens opacity by one month of age, several months prior to opacity appearing in the lens of SPARC and B-crystalin knockout mice. Analysis of the data, collectively, indicates that in vivo SPARC and B-crystalin (a small heat-shock protein and molecular chaperone) act in concert to promote folding and stabilization of lens ECM components (Emerson et al., 2006).
Recent studies report that two other extracellular calcium-binding glycoproteins, osteopontin (OPN) and dentin matrix protein-1 (DMP1), are either internalized or retained inside cells (Ye et al., 2005). OPN has been shown to co-localize with CD44 in fibroblasts and macrophages at their leading edge, promoting directional chemotaxis-mediated migration (Zohar et al., 2000; Sodek et al., 2002; Suzuki et al., 2002). In addition to a role in regulating nucleation of hydroxyapatite, DMP-1 also acts as a component of the nuclear transcription machinery responsible for the activation of osteoblast-specific genes in undifferentiated osteoblasts (Narayanan et al., 2004). It is interesting to note that nuclear translocation for SPARC has been observed for embryonic cells (Yan et al., 2005), and that full-length SPARC activates high-level expression of reporter genes in our yeast two-hybrid studies (unpublished). Hence, the idea that SIBLING family members and SPARC functions are restricted to the extracellular environment must now be reevaluated (Sodek et al., 2000, 2002).
Although the evidence presented in this review supports a chaperone role for SPARC in the formation of fibrillar as well as other types of collagens, much remains to be discovered before the complex series of molecular and cellular events—ensuring that collagens are properly folded, secreted, and assembled into their diverse supramolecular complexes—can be deciphered. While our focus has been on a direct role for SPARC as a chaperone, it is equally possible that SPARC may also regulate collagen homeostasis by interactions with intracellular components, such as tubulin and ILK, and by regulating the activity of growth factors, matrix remodeling proteins, and other matrix elements. Hence, unlocking the secrets of this enigmatic molecule, which may have first appeared during the transition from unicellular to multicellular organisms, will likely uncover some important insights into its relationship with collagen.
In summary, based on both evolutionary evidence and the lessons learned with organisms amenable to genetic studies, we hypothesize that an ancient function of SPARC that has been conserved in evolution is to enhance collagen triple-helix stability and secretion and supramolecular assembly in the extracellular environment. However, definitive proof of a novel collagen-specific chaperone role will require more comprehensive studies, including: mapping the precise intracellular distribution of SPARC relative to procollagens, investigating their interactions inside cells, analyzing the effects of the absence of SPARC on endoplasmic reticulum-mediated collagen degradation, and studying the influence of SPARC on collagen fibrillogenesis.
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FOOTNOTES |
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Received April 24, 2006; Accepted August 23, 2006
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Barker TH, Framson P, Puolakkainen PA, Reed M, Funk SE, Sage EH (2005b). Matricellular homologs in the foreign body response: hevin suppresses inflammation, but hevin and SPARC together diminish angiogenesis. Am J Pathol 166:923–933.
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