title: Functions of lumican and fibromodulin: lessons from knockout mice.
abstract: Lumican and fibromodulin are collagen-binding leucine-rich proteoglycans widely distributed in interstitial connective tissues. The phenotypes of lumican-null (Lum(-/-)), Fibromodulin-null (Fmod(-/-)) and compound double-null (Lum(-/-)Fmod(-/-)) mice identify a broad range of tissues where these two proteoglycans have overlapping and unique roles in modulating the extracellular matrix and cellular behavior. The lumican-deficient mice have reduced corneal transparency and skin fragility. The Lum(-/-)Fmod(-/-) mice are smaller than their wildtype littermates, display gait abnormality, joint laxity and age-dependent osteoarthritis. Misaligned knee patella, severe knee dysmorphogenesis and extreme tendon weakness are the likely cause for joint-laxity. Fibromodulin deficiency alone leads to significant reduction in tendon stiffness in the Lum(+/+)Fmod(-/-) mice, with further loss in stiffness in a lumican gene dose-dependent way. At the level of ultrastructure, the Lum(-/-) cornea, skin and tendon show irregular collagen fibril contours and increased fibril diameter. The Fmod(-/-) tendon contains irregular contoured collagen fibrils, with increased frequency of small diameter fibrils. The tendons of Lum(-/-)Fmod(-/-) have an abnormally high frequency of small and large diameter fibrils indicating a de-regulation of collagen fibril formation and maturation. 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
authors.affiliation: Departments of Medicine, Cell Biology and Ophthalmology, Johns Hopkins University, Baltimore, MD 21205, USA. schakrav@jhmi.edu
authors.forename: Shukti
authors.initials: S
authors.lastname: Chakravarti
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D011508:Chondroitin Sulfate Proteoglycans / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D003240:Connective Tissue Diseases / Q000235:genetics / Q000503:physiopathology; D003315:Cornea / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D000071235:Fibromodulin; D015870:Gene Expression; D007632:Keratan Sulfate / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000071234:Lumican; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011509:Proteoglycans; D012867:Skin / Q000378:metabolism; D013710:Tendons / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002352:Carrier Proteins; D011508:Chondroitin Sulfate Proteoglycans; D016326:Extracellular Matrix Proteins; C000604332:Fmod protein, mouse; C000604307:Lum protein, mouse; D000071234:Lumican; D011509:Proteoglycans; D000071235:Fibromodulin; D003094:Collagen; D007632:Keratan Sulfate