Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition.
Tenascin-X is a large extracellular matrix protein of unknown function. Tenascin-X deficiency in humans is associated with Ehlers-Danlos syndrome, a generalized connective tissue disorder resulting from altered metabolism of the fibrillar collagens. Because TNXB is the first Ehlers-Danlos syndrome gene that does not encode a fibrillar collagen or collagen-modifying enzyme, we suggested that tenascin-X might regulate collagen synthesis or deposition. To test this hypothesis, we inactivated Tnxb in mice. Tnxb-/- mice showed progressive skin hyperextensibility, similar to individuals with Ehlers-Danlos syndrome. Biomechanical testing confirmed increased deformability and reduced tensile strength of their skin. The skin of Tnxb-/- mice was histologically normal, but its collagen content was significantly reduced. At the ultrastructural level, collagen fibrils of Tnxb-/- mice were of normal size and shape, but the density of fibrils in their skin was reduced, commensurate with the reduction in collagen content. Studies of cultured dermal fibroblasts showed that although synthesis of collagen I by Tnxb-/- and wildtype cells was similar, Tnxb-/- fibroblasts failed to deposit collagen I into cell-associated matrix. This study confirms a causative role for TNXB in human Ehlers-Danlos syndrome and suggests that tenascin-X is an essential regulator of collagen deposition by dermal fibroblasts.
Mao
Jau Ren
JR
Department of Pediatrics, University of California, Laurel Heights Campus, 3333 California Street, Box 1245, San Francisco, California 94118, USA.
Taylor
Glen
G
Dean
Willow B
WB
Wagner
Diane R
DR
Afzal
Veena
V
Lotz
Jeffrey C
JC
Rubin
Edward M
EM
Bristow
James
J
D000818:Animals; D003094:Collagen / Q000378:metabolism*; D004535:Ehlers-Danlos Syndrome / Q000235:genetics*; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011995:Recombination, Genetic; D012879:Skin Physiological Phenomena; D019063:Tenascin / Q000172:deficiency* / Q000235:genetics*; D013997:Time Factors
D019063:Tenascin; C081865:tenascin X; D003094:Collagen