Type Xl collagen plays important roles in controlling the microstructural organization and composition of articular cartilage. The long-term objective of this project is to determine how a type Xl collagen gene mutation contributes to articular cartilage destruction in osteoarthritis (OA). Mice heterozygous for a mutated sequence in the Col11a1 gene appear developmentally normal, but develop premature onset of OA. Our preliminary studies demonstrate that this collagen defect gives rise to local decreased cartilage stiffness and associated local expression of OA. Thus, we hypothesize that mechanical factors initiate OA in this model, through functional changes that expose the cartilage extracellular matrix to altered stresses and strains upon loading. We propose a mechanism for the mechanical induction of OA in this transgenic mouse model, whereby expression of the mutated type Xl collagen gene product leads to: (1) changes in cartilage tensile properties associated with modifications in collagen fiber organization; and (2) changes in cartilage compressive properties associated with modified proteoglycan content. We further propose that the type Xl collagen gene mutation affects the more highly organized regions of mouse articular cartilage, i.e., superficial zone. Studies of knee and hip joint cartilage will be performed at 1 month of age to quantify early changes that may predispose the joints to OA. Cartilage tensile properties will be quantified using an osmotic loading method, and collagen fiber orientation will be measured using optical birefringence. Cartilage compressive properties will be quantified with indentation tests and negative fixed charge density from densitometric measures of Safranin-O staining, as a measure of tissue S-GAG content. Cartilage will be compared between sites with a highly organized superficial zone (i.e., femoral condyle and femoral head), and those with a more randomly oriented collagen network (i.e., tibial plateau). To characterize the time course of cartilage destruction in wild-type and mutant joints, we will quantify histomorphometric grade, cartilage protein and/or mRNA levels of relevant proteinases, cytokines and precursors to inflammatory mediators in mice up to 9 months of age. Completion of this study may reveal the mechanism by which this collagen mutation contributes to OA and will illustrate the temporal interplay between mechanical stimuli, proteolysis and inflammation involved in OA development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045644-05
Application #
6650384
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Tyree, Bernadette
Project Start
1999-02-01
Project End
2004-09-30
Budget Start
2003-07-01
Budget End
2004-09-30
Support Year
5
Fiscal Year
2003
Total Cost
$281,041
Indirect Cost
Name
Duke University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Jing, Liufang; So, Stephen; Lim, Shaun W et al. (2012) Differential expression of galectin-1 and its interactions with cells and laminins in the intervertebral disc. J Orthop Res 30:1923-31
Cao, Li; Youn, Inchan; Guilak, Farshid et al. (2006) Compressive properties of mouse articular cartilage determined in a novel micro-indentation test method and biphasic finite element model. J Biomech Eng 128:766-71
Guilak, Farshid; Alexopoulos, Leonidas G; Upton, Maureen L et al. (2006) The pericellular matrix as a transducer of biomechanical and biochemical signals in articular cartilage. Ann N Y Acad Sci 1068:498-512
Alexopoulos, Leonidas G; Williams, Gregory M; Upton, Maureen L et al. (2005) Osteoarthritic changes in the biphasic mechanical properties of the chondrocyte pericellular matrix in articular cartilage. J Biomech 38:509-17
Alexopoulos, Leonidas G; Setton, Lori A; Guilak, Farshid (2005) The biomechanical role of the chondrocyte pericellular matrix in articular cartilage. Acta Biomater 1:317-25
Flahiff, Charlene M; Kraus, Virginia B; Huebner, Janet L et al. (2004) Cartilage mechanics in the guinea pig model of osteoarthritis studied with an osmotic loading method. Osteoarthritis Cartilage 12:383-8
Setton, Lori A; Chen, Jun (2004) Cell mechanics and mechanobiology in the intervertebral disc. Spine (Phila Pa 1976) 29:2710-23
Kraus, Virginia B; Huebner, Janet L; Stabler, Thomas et al. (2004) Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model. Arthritis Rheum 50:1822-31
Xu, L; Flahiff, C M; Waldman, B A et al. (2003) Osteoarthritis-like changes and decreased mechanical function of articular cartilage in the joints of mice with the chondrodysplasia gene (cho). Arthritis Rheum 48:2509-18
Elliott, Dawn M; Narmoneva, Daria A; Setton, Lori A (2002) Direct measurement of the Poisson's ratio of human patella cartilage in tension. J Biomech Eng 124:223-8

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