The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions. Proteoglycans act as tissue organizers, influence cell growth and the maturation of specialized tissues, play a role as biological filters and modulate growth-factor activities, regulate collagen fibrillogenesis and skin tensile strength, affect tumor cell growth and invasion, and influence corneal transparency and neurite outgrowth. Additional roles, derived from studies of mutant animals, indicate that certain proteoglycans are essential to life whereas others might be redundant. The review focuses on the most recent genetic and molecular biological studies of the matrix proteoglycans, broadly defined as proteoglycans secreted into the pericellular matrix. Special emphasis is placed on the molecular organization of the protein core, the utilization of protein modules, the gene structure and transcriptional control, and the functional roles of the various proteoglycans. When possible, proteoglycans have been grouped into distinct gene families and subfamilies offering a simplified nomenclature based on their protein core design. The structure-function relationship of some paradigmatic proteoglycans is discussed in depth and novel aspects of their biology are examined.

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Matrix Proteoglycans: From Molecular Design to Cellular Function

Decorin is a member of the expanding group of widely distributed small leucine-rich proteoglycans that are expected to play important functions in tissue assembly. We report that mice harboring a targeted disruption of the decorin gene are viable but have fragile skin with markedly reduced tensile strength. Ultrastructural analysis revealed abnormal collagen morphology in skin and tendon, with coarser and irregular fiber outlines. Quantitative scanning transmission EM of individual collagen fibrils showed abrupt increases and decreases in mass along their axes, thereby accounting for the irregular outlines and size variability observed in cross-sections. The data indicate uncontrolled lateral fusion of collagen fibrils in the decorindeficient mice and provide an explanation for the reduced tensile strength of the skin. These findings demonstrate a fundamental role for decorin in regulating collagen fiber formation in vivo.

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Targeted Disruption of Decorin Leads to Abnormal Collagen Fibril Morphology and Skin Fragility

The large size of many novel therapeutics impairs their transport through the tumor extracellular matrix and thus limits their therapeutic effectiveness. We propose that extracellular matrix composition, structure, and distribution determine the transport properties in tumors. Furthermore, because the characteristics of the extracellular matrix largely depend on the tumor–host interactions, we postulate that diffusion of macromolecules will vary with tumor type as well as anatomical location. Diffusion coefficients of macromolecules and liposomes in tumors growing in cranial windows (CWs) and dorsal chambers (DCs) were measured by fluorescence recovery after photobleaching. For the same tumor types, diffusion of large molecules was significantly faster in CW than in DC tumors. The greater diffusional hindrance in DC tumors was correlated with higher levels of collagen type I and its organization into fibrils. For molecules with diameters comparable to the interfibrillar space the diffusion was 5- to 10-fold slower in DC than in CW tumors. The slower diffusion in DC tumors was associated with a higher density of host stromal cells that synthesize and organize collagen type I. Our results point to the necessity of developing site-specific drug carriers to improve the delivery of molecular medicine to solid tumors.

https://www.pnas.org/content/pnas/98/8/4628.full.pdf

Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors.

The focus of this review is on conceptual and functional advances in our understanding of the small leucine-rich proteoglycans. These molecules belong to an expanding gene class whose distinctive feature is a structural motif, called the leucine-rich repeat, found in an increasing number of intracellular and extracellular proteins with diverse biological attributes. Three-dimensional modeling of their prototype protein core proposes a flexible, arch-shaped binding surface suitable for strong and distinctive interactions with ligand proteins. Changes in the properties of individual proteoglycans derive from amino acid substitutions in the less conserved surface residues, changes in the number and length of the leucine-rich repeats, and/or variation in glycosylation. These proteoglycans are tissue organizers, orienting and ordering collagen fibrils during ontogeny and in pathological processes such as wound healing, tissue repair, and tumor stroma formation. These properties are rooted in their bifunctional character: the protein moiety binding collagen fibrils at strategic loci, the microscopic gaps between staggered fibrils, and the highly charged glycosaminoglycans extending out to regulate interfibrillar distances and thereby establishing the exact topology of fibrillar collagens in tissues. These proteoglycans also interact with soluble growth factors, modulate their functional activity, and bind to cell surface receptors. The latter interaction affects cell cycle progression in a variety of cellular systems and could explain the purported changes in the expression of these gene products around the invasive neoplastic cells and in regenerating tissues.

The family of the small leucine-rich proteoglycans: key regulators of matrix assembly and cellular growth.

Reduced extracellular matrix in mammalian sclera with induced myopia

Corneal transparency is dependent upon the development of an organized extracellular matrix containing small diameter collagen fibrils with regular spacing, organized as orthogonal lamellae. Proteoglycan-collagen interactions have been implicated in the regulation of collagen fibrillogenesis and matrix assembly. To determine the role of dermatan sulfate proteoglycan in the development and organization of the secondary corneal stroma, its synthesis was disrupted using beta-D xyloside. The secondary corneal stroma contains two different proteoglycans, dermatan sulfate and keratan sulfate proteoglycan. beta-D xyloside interferes with xylose-mediated O-linked proteoglycan synthesis, and thus disrupts dermatan sulfate proteoglycan synthesis. Corneal keratan sulfate proteoglycan, a mannose-mediated N-linked proteoglycan, should not be altered. Biochemical analysis of corneas treated both in vitro and in ovo revealed a reduced synthesis of normally glycosylated dermatan sulfate proteoglycans and an increased synthesis of free xyloside-dermatan sulfate glycosaminoglycans. Keratan sulfate proteoglycan synthesis was unaltered in both cases. Corneal stromas were studied using histochemistry and electron microscopy after in ovo treatment with beta-D xyloside. The observed biochemical alterations in dermatan sulfate proteoglycans translated into disruptions in the organization of beta-D xyloside-treated stromas. There was a reduction in the histochemical staining of proteoglycans, but no alteration in collagen fibril diameter. In addition, focal alterations in collagen fibril packing, and a disruption of lamellar organization were observed in beta-D xyloside-treated corneas. These data suggest that dermatan sulfate proteoglycans are not involved in the regulation of corneal collagen fibril diameter, but are important in the fibril-fibril spacing as well as in lamellar organization, and cohesiveness.

D.E. Birk

Papers

beta-D xyloside alters dermatan sulfate proteoglycan synthesis and the organization of the developing avian corneal stroma.