Lumican Regulates Collagen Fibril Assembly: Skin Fragility and Corneal Opacity in the Absence of Lumican

Abstract

Lumican, a prototypic leucine-rich proteoglycan with keratan sulfate side chains, is a major component of the cornea, dermal, and muscle connective tissues. Mice homozygous for a null mutation in lumican display skin laxity and fragility resembling certain types of Ehlers-Danlos syndrome. In addition, the mutant mice develop bilateral corneal opacification. The underlying connective tissue defect in the homozygous mutants is deregulated growth of collagen fibrils with a significant proportion of abnormally thick collagen fibrils in the skin and cornea as indicated by transmission electron microscopy. A highly organized and regularly spaced collagen fibril matrix typical of the normal cornea is also missing in these mutant mice. This study establishes a crucial role for lumican in the regulation of collagen assembly into fibrils in various connective tissues. Most importantly, these results provide a definitive link between a necessity for lumican in the development of a highly organized collagenous matrix and corneal transparency.

Collagen fibril assembly during postnatal development and dysfunctional regulation in the lumican‐deficient murine cornea

“…Lumican, a major proteoglycan of the cornea, is critical to the establishment of normal corneal structure and function. In the lumican knockout mouse model, the corneal stroma develops 60% of its normal thickness and fails to acquire wild type transparent properties (Chakravarti et al, 1998. These studies demonstrate that the sharp increase in stromal thickness observed before eyelid opening in the normal cornea does not occur in lumican-null mice (Song et al, 2003).…”

“…This also followed the pattern of reduced lumican mRNA levels at these later stages. We do not believe that the reduced reactivity at P10 and P12 was due to reduced antibody penetration and staining of the core protein in the fully glycosaminoglycanated form, because this antibody, characterized in the past, has not shown reduced staining of mature proteoglycan versus deglycosylated core protein (Chakravarti et al, 1998).…”

“…Earlier structural studies were done using adult lumican knockout mice and demonstrated defects in collagen fibril structure and organization in the adult posterior stroma (Chakravarti et al, 1998Saika et al, 2000). Here, we focused on analyzing the developmental acquisition of this phenotype.…”

“…Each of these four leucine-rich proteoglycans have been "knocked out" in the mouse (Danielson et al, 1997;Chakravarti et al, 1998;Saika et al, 2000;Tasheva et al, 2002;Liu et al, 2003) and all demonstrate abnormal connective tissue phenotypes in various organs and tissues. However, only mice deficient in lumican have a significant disruption in corneal collagen fibril architecture.…”

“…However, only mice deficient in lumican have a significant disruption in corneal collagen fibril architecture. The fibrils in adult lumicannull corneas show a wide range in diameter and contain a population of abnormally large fibrils with irregular contours (Chakravarti et al, 1998. In addition, alterations in fibril packing are detected by X-ray diffraction analysis (Quantock et al, 2001).…”