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

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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; Birk, David E; Chakravarti, Shukti.

In: Journal of Biological Chemistry, Vol. 277, No. 38, 2002, p. 35532-35540.

Research output: Contribution to journalArticle

Harvard

Jepsen, KJ, Wu, F, Peragallo, JH, Paul, J, Roberts, L, Ezura, Y, Oldberg, Å, Birk, DE & Chakravarti, S 2002, 'A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice', Journal of Biological Chemistry, vol. 277, no. 38, pp. 35532-35540. https://doi.org/10.1074/jbc.M205398200

APA

Jepsen, K. J., Wu, F., Peragallo, J. H., Paul, J., Roberts, L., Ezura, Y., Oldberg, Å., Birk, D. E., & Chakravarti, S. (2002). A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice. Journal of Biological Chemistry, 277(38), 35532-35540. https://doi.org/10.1074/jbc.M205398200

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MLA

Vancouver

Author

Jepsen, Karl J ; Wu, Feng ; Peragallo, Jason H ; Paul, Jennifer ; Roberts, Luke ; Ezura, Yoichi ; Oldberg, Åke ; Birk, David E ; Chakravarti, Shukti. / A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 38. pp. 35532-35540.

RIS

TY - JOUR

T1 - A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice

AU - Jepsen, Karl J

AU - Wu, Feng

AU - Peragallo, Jason H

AU - Paul, Jennifer

AU - Roberts, Luke

AU - Ezura, Yoichi

AU - Oldberg, Åke

AU - Birk, David E

AU - Chakravarti, Shukti

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.M205398200

DO - 10.1074/jbc.M205398200

M3 - Article

VL - 277

SP - 35532

EP - 35540

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 38

ER -