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A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice

Jepsen, Karl J; Wu, Feng; Peragallo, Jason H; Paul, Jennifer; Roberts, Luke; Ezura, Yoichi; Oldberg, Åke LU ; Birk, David E and Chakravarti, Shukti (2002) In Journal of Biological Chemistry 277(38). p.35532-35540
Abstract
Lumican and fibromodulin regulate the assembly of collagens into higher order fibrils in connective tissues. Here, we show that mice deficient in both of these proteoglycans manifest several clinical features of Ehlers-Danlos syndrome. The Lum(-/-)Fmod(-/-) mice are smaller than their wild type littermates and display gait abnormality, joint laxity, and age-dependent osteoarthritis. Misaligned knee patella, severe knee dysmorphogenesis, and extreme tendon weakness are the likely causes for joint laxity in the double-nulls. 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. At the protein level, we show marked... (More)
Lumican and fibromodulin regulate the assembly of collagens into higher order fibrils in connective tissues. Here, we show that mice deficient in both of these proteoglycans manifest several clinical features of Ehlers-Danlos syndrome. The Lum(-/-)Fmod(-/-) mice are smaller than their wild type littermates and display gait abnormality, joint laxity, and age-dependent osteoarthritis. Misaligned knee patella, severe knee dysmorphogenesis, and extreme tendon weakness are the likely causes for joint laxity in the double-nulls. 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. At the protein level, we show marked increase of lumican in Fmod(-/-) tendons, which may partially rescue the tendon phenotype in this genotype. These results establish fibromodulin as a key regulator and lumican as a modulator of tendon strength. A disproportionate increase in small diameter immature collagen fibrils and a lack of progression to mature, large diameter fibrils in the Fmod(-/-) background may constitute the underlying cause of tendon weakness and suggest that fibromodulin aids fibril maturation. 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
277
issue
38
pages
35532 - 35540
publisher
ASBMB
external identifiers
  • wos:000178117000112
  • scopus:0037144516
ISSN
1083-351X
DOI
10.1074/jbc.M205398200
language
English
LU publication?
yes
id
0b5d5694-8d0a-424b-91ce-8943b0990fb3 (old id 328343)
date added to LUP
2007-10-24 16:06:29
date last changed
2017-09-24 03:38:29
@article{0b5d5694-8d0a-424b-91ce-8943b0990fb3,
  abstract     = {Lumican and fibromodulin regulate the assembly of collagens into higher order fibrils in connective tissues. Here, we show that mice deficient in both of these proteoglycans manifest several clinical features of Ehlers-Danlos syndrome. The Lum(-/-)Fmod(-/-) mice are smaller than their wild type littermates and display gait abnormality, joint laxity, and age-dependent osteoarthritis. Misaligned knee patella, severe knee dysmorphogenesis, and extreme tendon weakness are the likely causes for joint laxity in the double-nulls. 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. At the protein level, we show marked increase of lumican in Fmod(-/-) tendons, which may partially rescue the tendon phenotype in this genotype. These results establish fibromodulin as a key regulator and lumican as a modulator of tendon strength. A disproportionate increase in small diameter immature collagen fibrils and a lack of progression to mature, large diameter fibrils in the Fmod(-/-) background may constitute the underlying cause of tendon weakness and suggest that fibromodulin aids fibril maturation. 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.},
  author       = {Jepsen, Karl J and Wu, Feng and Peragallo, Jason H and Paul, Jennifer and Roberts, Luke and Ezura, Yoichi and Oldberg, Åke and Birk, David E and Chakravarti, Shukti},
  issn         = {1083-351X},
  language     = {eng},
  number       = {38},
  pages        = {35532--35540},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice},
  url          = {http://dx.doi.org/10.1074/jbc.M205398200},
  volume       = {277},
  year         = {2002},
}