Dysfunctional tendon collagen fibrillogenesis in collagen VI null mice.
Tendons are composed of fibroblasts and collagen fibrils. The fibrils are organized uniaxially and grouped together into fibers. Collagen VI is a non-fibrillar collagen expressed in developing and adult tendons. Human collagen VI mutations result in muscular dystrophy, joint hyperlaxity and contractures. The purpose of this study is to determine the functional roles of collagen VI in tendon matrix assembly. During tendon development, collagen VI was expressed throughout the extracellular matrix, but enriched around fibroblasts and their processes. To analyze the functional roles of collagen VI a mouse model with a targeted inactivation of Col6a1 gene was utilized. Ultrastructural analysis of Col6a1-/- versus wild type tendons demonstrated disorganized extracellular micro-domains and associated collagen fibers in the Col6a1-/- tendon. In Col6a1-/- tendons, fibril structure and diameter distribution were abnormal compared to wild type controls. The diameter distributions were shifted significantly toward the smaller diameters in Col6a1-/- tendons compared to controls. An analysis of fibril density (number/μm(2)) demonstrated a ~2.5 fold increase in the Col6a1-/- versus wild type tendons. In addition, the fibril arrangement and structure were aberrant in the peri-cellular regions of Col6a1-/- tendons with frequent very large fibrils and twisted fibrils observed restricted to this region. The biomechanical properties were analyzed in mature tendons. A significant decrease in cross-sectional area was observed. The percent relaxation, maximum load, maximum stress, stiffness and modulus were analyzed and Col6a1-/- tendons demonstrated a significant reduction in maximum load and stiffness compared to wild type tendons. An increase in matrix metalloproteinase activity was suggested in the absence of collagen VI. This suggests alterations in tenocyte expression due to disruption of cell-matrix interactions. The changes in expression may result in alterations in the peri-cellular environment. In addition, the absence of collagen VI may alter the sequestering of regulatory molecules such as leucine rich proteoglycans. These changes would result in dysfunctional regulation of tendon fibrillogenesis indirectly mediated by collagen VI.
Department of Pathology & Cell Biology, University of South Florida College of Medicine, Tampa, FL 33612-4799, USA.
Yayoi
Y
Izu
Heather L
HL
Ansorge
Guiyun
G
Zhang
Louis J
LJ
Soslowsky
Paolo
P
Bonaldo
Mon-Li
ML
Chu
David E
DE
Birk
D000818:Animals; D024142:Collagen Type VI / Q000235:genetics*; D024022:Fibrillar Collagens / Q000737:chemistry* / Q000378:metabolism; D005347:Fibroblasts / Q000737:chemistry / Q000473:pathology; D006244:Hardness; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D020836:Protein Structure, Quaternary; D013710:Tendons / Q000737:chemistry / Q000254:growth & development / Q000473:pathology*; D013718:Tensile Strength
D024142:Collagen Type VI; D024022:Fibrillar Collagens; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2