| Summary: | Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2005. === Includes bibliographical references. === Acute traumatic joint injury in young adults leads to an increased risk for the development of osteoarthritis (OA) later in life irrespective of surgical intervention to stabilize the injured joint. Although the mechanism by which injury leads to joint degeneration remains to be elucidated, several injury-related factors may contribute to the development of OA. These factors include but are not limited to altered mechanical loading and initiation of a cellular response in cartilage or other joint tissues at the time of the injury. Three in vitro models of joint injury were investigated to separately evaluate the effects on cartilage of mechanical overloading and damage to joint capsule and synovial lining. Models of injury included (1) mechanical injury lto cartilage explants alone, (2) co-culture of normal cartilage explants with an excised specimen of joint capsule tissue, and (3) co-culture of mechanically injured cartilage explants with excised joint capsule tissue. These models have been shown previously to result in matrix damage and decreased biosynthesis by the chondrocytes. We measured gene expression levels of matrix molecules and matrix proteases and found them to be expressed in control cartilage at levels ranging over five orders of magnitude, and to be differentially regulated in these three models of joint injury. === (cont.) Expression of matrix molecules including collagen II and aggrecan were unaffected by injurious compression or co-culture with joint capsule tissue during the first 24 hours; however, the combination of injurious compression followed by co-culture resulted in a -50% decrease in expression by 24 hours. Matrix proteases aggrecanase-2 (ADAMTS-5) and stromelysin (MMP-3) showed increased expression of 40-250-fold by 12 hours following injurious compression and 6-12-fold during 24 hours of co-culture with joint capsule tissue. Aggrecanase-1 (ADAMTS-4) and collagenase-3 (MMP-13) showed larger magnitude increases in expression during co-culture (6-8-fold; 6-24 hours) compared to injurious compression (2-4-fold; 6-24 hours). Expression of transcription factors, c-fos and c-jun, was rapidly increased by injurious compression (40-100-fold within one hour) but was less affected by co-culture with joint capsule tissue (increased 3-5-fold; 1-24 hours). Expression level results displayed a general trend toward matrix degradation in the models of joint injury with specific differences apparent between the models. Analysis of matrix protein fragments in the same injury models showed cleavage of aggrecan at the aggrecanase site in the interglobular domain by 16 days following injurious compression and during co-culture with joint capsule tissue. === (cont.) Equilibrium and dynamic stiffness of cartilage explants were decreased by 30-35% immediately after injurious compression but were unaffected through 16 days of co-culture with joint capsule tissue. Specific changes in gene expression and activity of matrix proteases observed in these injury models may be indicative of some of the molecules responsible in the initial phase of cartilage degradation observed clinically following joint injury. === Jennifer H. Lee. === Ph.D.
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