SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury (original) (raw)

Vertebrate SPARC binds to a number of different ECM components including thrombospondin 1, vitronectin, entactin/nidogen, fibrillar collagens (types I, II, III, and V), and collagen type IV, the prevalent collagen in basement membranes (1). Therefore, SPARC has the potential to contribute to the organization of matrix in connective tissue as well as basement membranes. Interestingly, SPARC is expressed abundantly in basement membranes and in capsules that surround a variety of organs and tissues. In this regard, SPARC-null mice display early cataractogenesis, a phenotype with 100% penetrance (2). Transmission electron microscopy of lens epithelial cells in SPARC-null mice shows an intrusion of cellular processes into the basement membrane of the lens capsule, whereas wild-type lens epithelial cells exhibit a precise border at the cell-matrix interface (3). We have proposed that this phenotype reflects aberrant cell behavior or differentiation resulting from altered composition or structure of the basement membrane formed in the absence of SPARC.

With respect to connective tissue, preliminary transmission electron microscopy of dermal collagen fibers also revealed differences between wild-type and SPARC-null mice. Whereas collagen fibrils from wild-type skin exhibit a variety of large and small diameters, as observed previously in normal adult animals, SPARC-null fibrils are smaller and more uniform in diameter (A.D. Bradshaw et al., unpublished results). Differences in collagen fibril size are consistent with our primary observation that the skin of SPARC-null mice is more easily stretched and weaker in tensile strength than that of wild-type mice. Apparently the absence of SPARC affects collagen fibrillogenesis, most likely during development, although confirmation of this idea awaits completion of experiments in which a developmental time course of collagen fibril assembly will be analyzed. Whether SPARC acts to affect fibrillogenesis directly through its collagen-binding capacity or by another mechanism is unknown. However, in connective tissues of _mov_-13 mice, which are deficient in collagen I, SPARC is not distributed in specific matrices that are known sites of SPARC deposition in wild-type embryos (1). In developing Xenopus, SPARC appears to be concentrated within the intersomitic furrows, a location known to be rich in collagen fibers (4).

Further evidence for the importance of SPARC in connective tissue is found in the curly tails of SPARC-null mice, a characteristic reminiscent of thrombospondin 2–null mice (5). Thrombospondin 2 is another matricellular protein with potential collagen-binding activity, as thrombospondin 2–null mice also display aberrant collagen fibrils in the skin and an abnormally flexible tail (5). In fact, a variety of ECM-associated components have been implicated in collagen fibrillogenesis by virtue of the phenotypic abnormalities observed in transgenic mice with targeted deletions of the genes for decorin, fibromodulin, lumican, and osteopontin, among others (6–8). Since some of these proteins and proteoglycans are known to affect collagen fibrillogenesis in vitro, phenotypic abnormalities in collagen fibrils were not unexpected in these animals. Others, such as SPARC and thrombospondin 2, proved to be more surprising. Clearly the assembly and regulation of collagen fibril size is a complex process about which a great deal remains to be learned.

Similar to vertebrate SPARC, C. elegans SPARC is encoded by a single gene, ost-1. Although there are both structural and functional differences between vertebrate and nematode SPARC, such as a reduced affinity for Ca2+, binding to both collagen types I and IV is conserved (1). SPARC in C. elegans is expressed primarily by body wall and sex muscle cells, although SPARC protein is also associated with the basement membrane of the pharynx, a tissue in which SPARC mRNA is not detected (9). A similar disparity between sites of synthesis and deposition has been noted in C. elegans for collagen IV, and in mouse, for SPARC (1). Thus, nematode SPARC appears to be transported extracellularly to basement membranes at some distance from its sites of synthesis, an observation suggesting a function for this protein in matrix organization or activity.

The capacity of SPARC to bind to a number of different ECM proteins provides a basis for the association of SPARC with both basement membranes and fibrous connective tissue. During development, when many ECMs are being laid down, higher levels of SPARC are observed (1). Subsequently, the expression of SPARC is restricted to sites of ECM turnover and is virtually undetectable in normal cells within their established ECM. In fact, Damjanovski et al. observed in Xenopus embryos that expression of SPARC decreased precipitously upon morphological differentiation of specific tissues (10).

Interestingly, SPARC is a substrate of transglutaminase, an enzyme that establishes covalent cross-links between proteins (11). Although the function of tissue transglutaminase in the stabilization of the ECM is not completely understood, strong evidence for its importance in matrix assembly and cell interaction with ECM is emerging (12). Possibly, expression of SPARC in response to injury or tissue remodeling is necessary to facilitate production of an ECM permissive for cell migration, proliferation, and differentiation. SPARC might substitute for other transglutaminase substrates that provide structural support in the ECM: for example, cross-linking of SPARC instead of fibronectin, another substrate of transglutaminase, could result in a more malleable matrix.