The Function of SPARC as a Mediator of Fibrosis

Abstract

Fibrosis is a common end-point of a number of different diseases such as hypertension, diabetes, liver cirrhosis, and those associated with chronic inflammation. Fibrosis is characterized by excessive deposition of extracellular matrix that interferes with normal tissue architecture and function. Increased expression of secreted protein acidic and rich in cysteine (SPARC) in fibrotic tissues has been reported in numerous studies. SPARC is a 43 kDa collagen-binding protein secreted from several different cell types into the extracellular matrix and has been shown to be anti-proliferative and counter-adhesive in vitro. SPARC is a matricellular protein; meaning SPARC is secreted into the extracellular space but does not serve a structural function. Instead, SPARC modulates interactions between cells and the surrounding extracellular matrix. In animal models of fibrotic disease and in human fibrotic tissues, elevated expression of SPARC has been reported in many tissues including heart, lungs, kidneys, liver, dermis, intestine, and eyes. In this review, we will summarize current studies that have examined the expression and functional importance of SPARC in various animal models of fibrosis and in human tissues. Although cellular mechanisms of SPARC in fibrosis remain to be fully elucidated, the studies summarized here provide impetus to further explore the efficacy of SPARC as a potential target for reducing fibrosis.

Keywords: Collagen; disease.; extracellular matrix; matricellular protein.

Fig. (1)

Hypothetical Model of Cellular Mechanisms of SPARC. SPARC binds procollagen as it is secreted from the cell (or procollagen is secreted bound by SPARC) and prevents interaction of procollagen with cellular receptors, such as DDR2 and integrin α₂β₁ (or others). Therefore, procollagen is appropriately processed and incorporated into collagen fibrils. In the absence of SPARC, procollagen accumulates at the cell surface and is inefficiently incorporated into the collagenous ECM, resulting in less total collagen and fewer thick collagen fibers.

Fig. (2)

SPARC-null Periodontal Ligament (PDL) is More Susceptible to Collagen Loss Following Lipopolysaccharide Induction of Inflammation. Mice were injected 3 times weekly for four weeks with lipopolysaccharide (LPS, C and D) or vehicle control: phosphate buffered saline (PBS, A and B). SPARC-null PDL (D) exhibited significant loss of collagen as compared to WT (C), white arrows (see ref. [28]). Furthermore, given one week to recover (no LPS injections), WT PDL (E) re-established baseline levels of collagen characterized by the presence of thick collagen fibers (orange/red-white arrows), whereas SPARC-null PDL (F) did not exhibit a return to base-line conditions as indicated by the abundance of thin collagen fibers in SPARC-null mice after one week of recovery (green- white arrows). B: bone, T: Tooth, PDL: Periodontal Ligament.