Disease relevance of Lum

• This study demonstrates that the collagen fibril-modifying proteoglycans, lumican and fibromodulin, are candidate genes and key players in the pathogenesis of certain types of Ehlers-Danlos syndrome and other connective tissue disorders [1].
• A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice [1].
• Retinal detachment was frequent in the double-null and rare in the lumican-null animals [2].
• Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican [3].
• The Lcn map site is in the region of a previously identified developmental mutant, eye blebs, affecting corneal morphology [4].
• Together, these data support a significant role for lumican and keratocan in a corneal inflammatory response with respect to edema, corneal clarity, and cellular infiltration [5].

High impact information on Lum

• In this issue of Cell, new evidence indicates that autophagy is used to for survival when intracellular nutrients are limited by growth factor deprivation (Lum et al., 2005) [6].
• The observed increased ratio of fibromodulin to lumican and a competition for the same binding site could mediate these transitions [7].
• In lumican-deficient tendons, alterations were observed early and the mature tendon was nearly normal [7].
• Fibromodulin-deficient tendons were comparable with the lumican-null in early developmental periods and acquired a severe phenotype by maturation [7].
• This study establishes a crucial role for lumican in the regulation of collagen assembly into fibrils in various connective tissues [3].

Biological context of Lum

• At the protein level, we show marked increase of lumican in Fmod(-/-) tendons, which may partially rescue the tendon phenotype in this genotype [1].
• The Lum(-/-) mouse shows increased proliferation and decreased apoptosis of stromal keratocytes during postnatal corneal maturation at the 10-day age [8].
• Apoptosis is also significantly down regulated in Lum(-/-) vis-à-vis Lum(+/+) mice during stromal wound healing in the adult 6-week age [8].
• Six primer pairs spanning intron-exon boundaries and coding regions were designed for the 3-exon 1804 base pair (bp) lumican gene [9].
• Lumican suppresses cell proliferation and aids Fas-Fas ligand mediated apoptosis: implications in the cornea [8].

Anatomical context of Lum

• Fibromodulin deficiency alone leads to significant reduction in tendon stiffness in the Lum(+/+)Fmod(-/-) mice, with further loss in stiffness in a Lum gene dose-dependent way [1].
• In the current study, we examined the effect of lumican overexpression in corneas of wild type mice [10].
• Lumican and fibromodulin regulate the assembly of collagens into higher order fibrils in connective tissues [1].
• Conversely, the cruciate ligaments of the knee showed both an increase in LUM content and considerable structural abnormalities including the tendency towards rupture [11].
• Biochemical and immunohistochemical investigation of FM-null articular cartilage showed a significant increase in tissue levels of lumican (LUM) [11].

Associations of Lum with chemical compounds

• Corneal lumican modified with keratan sulfate constitutes one of the major proteoglycans of the stroma [10].
• Lumican is an extracellular matrix glycoprotein widely distributed in mammalian connective tissues [10].
• Lumican and fibromodulin are collagen-binding leucine-rich proteoglycans widely distributed in interstitial connective tissues [12].
• The results indicate that the cysteine-rich domain of lumican is important in collagen fibrillogenesis and stromal matrix assembly [13].
• The N-terminus of the lumican protein contains consensus sequences for tyrosine sulfation [4].
• An exogenous recombinant lumican core protein increases lipopolysaccharide-mediated TNFalpha induction and partially rescues innate immune response in Lum(-/-) macrophages [14].

Physical interactions of Lum

• In tissues like the tendon, where both proteoglycans are present, fibromodulin may be required early in collagen fibrillogenesis to stabilize small-diameter fibril-intermediates and lumican may be needed at a later stage, primarily to limit lateral growth of fibrils[12]
• CONCLUSIONS: The data suggest that lumican binds FasL and facilitates induction of Fas [15].

Regulatory relationships of Lum

• The Lum(-/-) MEF fail to induce Fas upon treatment with Fas ligand [8].

Other interactions of Lum

• Corneas of lumican-null mice showed decreased keratocan [10].
• The MEF and the cornea of Lum(-/-) mice also show a dramatic decrease in Fas (CD95) [8].
• Biglycan and, less significantly, lumican were expressed in decidualized regions of the endometrium, but decorin was absent [16].
• The evidence suggests regulation of p21 by lumican in a p53-dependent way [8].
• In Tgfb2(-/-) mice, fewer keratocytes were found in stroma that has a decreased accumulation of ECM; for example, lumican, keratocan and collagen I were greatly diminished [17].

Analytical, diagnostic and therapeutic context of Lum

• The mouse lumican gene was isolated from a bacterial artificial chromosome mouse genomic DNA library and characterized by polymerase chain reaction and Southern hybridization [18].
• Northern hybridization and in situ hybridization indicate that in early stages of embryonic development, day 7 post coitus the embryo expresses little or no lumican [18].
• METHODS: Backscattering of light, a function of corneal haze and opacification, was determined regionally using in vivo confocal microscopy in lumican-deficient and wild-type control mice [19].
• Glycosidase digestion followed by Western blot analysis provided characterization of molecular properties of purified mouse corneal lumican [4].
• Recently, using the cDNA microarray technology we found lumican to be abundantly expressed during the mineralization and differentiation stages of the MC3T3-E1 development and not during the proliferation stage [20].

References