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2 Regulation of extracellular matrix and cell cycle in mice lacking the matricellular protein SPARC: You can believe your eyes

Matricellular proteins such as SPARC (secreted protein acidic and rich in cysteine), thrombospondins 1 & 2, tenascin C, and osteopontin function contextually to mediate interactions between cells and the extracellular matrix (ECM). Thus, they feature prominently in tissue morphogenesis, remodeling, and repair. On cultured cells, exogenous SPARC exhibits counteradhesive and/or anti-proliferative properties. The former effect is mediated in part by modulation of ECM production and inhibition of focal adhesion formation, whereas antiproliferation is attributed to: a) interactions between SPARC and growth factors that alter signaling through their cognate receptors, and b) decreases in cyclin A levels and in the activities of other proteins associated with G1/S. Many of the functions of SPARC or its various subdomains that were demonstrated in vitro have been confirmed in mice with a targeted deletion of the SPARC gene. For example, cells from these mice exhibit significantly enhanced rates of proliferation. Mesangial cells also show a diminished production of TGF-1 and reduced levels of collagen synthesis, relative to wild-type cells, that can be rescued by exogenous SPARC. The pleiotropic effects of TGF on ECM biosynthesis and cell cycle control might thus account for the responses of certain cells to SPARC. Moreover, all strains of mice lacking the SPARC gene develop early-onset cataracts associated with aberrant proliferation and differentiation of lens epithelial cells. Additional phenotypic alterations associated with aging, connective tissues, wound healing, and/or angiogenesis indicate an heretofore unanticipated significance for SPARC and for other matricellular proteins in the regulation of the morphogenesis and maintenance of certain organs and tissues.

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