title: Ocular and scleral alterations in gene-targeted lumican-fibromodulin double-null mice.
abstract: OBJECTIVE
  To elucidate the role of leucine-rich proteoglycans lumican and fibromodulin in the sclera.
  
  
  METHODS
  Lumican- and fibromodulin-null heterozygous mice were intercrossed to obtain wild-type (Lum(+/+)Fmod(+/+)), lumican-null (Lum(-/-)Fmod(+/+)), fibromodulin-null (Lum(+/+)Fmod(-/-)), and double-null (Lum(-/-)Fmod(-/-)) littermates. Axial length was measured on enucleated whole eyes, and ocular structural changes were examined by histology. The morphology of collagen fibrils in the sclera was examined by transmission electron microscopy (TEM).
  
  
  RESULTS
  Compared with the ocular axial length in wild type mice, the axial length was increased by 10% in Lum(-/-)Fmod(-/-) (P = 0.02) mice. Retinal detachment was frequent in the double-null and rare in the lumican-null animals. Compared with the wild-type sclera, the sclera in all null mutants was significantly thinner with fewer lamellae (P < 0.05). The double-null sclera contained abnormally large-diameter (120-160 nm) and small-diameter (30-60 nm) collagen fibrils, whereas the fibromodulin-null sclera was enriched for the small-diameter fibrils. The collagen fibril diameter distribution in the lumican-null sclera was similar to that of the wild-type.
  
  
  CONCLUSIONS
  An increase in small-diameter fibrils in the fibromodulin-null sclera suggests a key role for fibromodulin in the maturation and assembly of scleral collagen fibrils. That fibril diameter distribution in the lumican-null sclera was comparable to that in the wild type, but severely disrupted in the double null, suggests a role for lumican that is crucial in the absence of fibromodulin. The eyes of Lum(-/-)Fmod(-/-) mice show certain features of high myopia: increased axial length, thin sclera, and retinal detachment. Mutations or altered expression of these proteoglycans may contribute to myopia in humans.
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA. schakrav@jhmi.edu
authors.forename: Shukti
authors.initials: S
authors.lastname: Chakravarti
authors.forename: Jennifer
authors.initials: J
authors.lastname: Paul
authors.forename: Luke
authors.initials: L
authors.lastname: Roberts
authors.forename: Inna
authors.initials: I
authors.lastname: Chervoneva
authors.forename: Ake
authors.initials: A
authors.lastname: Oldberg
authors.forename: David E
authors.initials: DE
authors.lastname: Birk
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000502:physiology*; D011508:Chondroitin Sulfate Proteoglycans / Q000502:physiology*; D016326:Extracellular Matrix Proteins; D005260:Female; D024022:Fibrillar Collagens / Q000648:ultrastructure; D000071235:Fibromodulin; D018390:Gene Targeting; D007632:Keratan Sulfate / Q000502:physiology*; D000071234:Lumican; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009216:Myopia / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D011509:Proteoglycans; D012163:Retinal Detachment / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012590:Sclera / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D015422:Scleral Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D011508:Chondroitin Sulfate Proteoglycans; D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; D024022:Fibrillar Collagens; C000604332:Fmod protein, mouse; C000604306:LUM protein, human; C000604307:Lum protein, mouse; D000071234:Lumican; D011509:Proteoglycans; D000071235:Fibromodulin; D007632:Keratan Sulfate