There are approximately 200,000 anterior cruciate ligament (ACL) injuries reported yearly in the United States. Complete ACL injuries often require operative reconstruction using autograft or allograft tissue. There are disadvantages in each reconstruction graft choice, thus alternatives to facilitate primary ACL repair or tissue engineering of ligament replacement must be developed. This development requires a clear understanding of the effect of mechanical stimuli on the structure and function of the ACL. Ligament development, structure, function and response to injury depend on exposure to mechanical stimuli. The organization and turnover of matrix by ligament fibroblasts determine the material properties and mechanical behavior if the ACL in vivo. The goals of this research are to determine the effects of mechanical stimuli on matrix synthesis and turnover in ACL fibroblasts and to identify signal transduction factors responsible for regulation of these processes using in vitro and in vivo model systems. We hypothesize that: 1. Stress deprivation in ACL fibroblasts results in upregulation of matrix degrading enzymes and tensile load stimulates matrix synthesis and down regulates matrix-degrading enzymes. 2. Mechanical regulation of matrix and MMP gene expression involves the integrin/cytoskeletal/intermediate filament/FAK pathway, stress activated ion channels and/or SAPK/JNK signal transduction pathways. 3. Creation of an in vivo partial ACL transection model will confirm the results obtained using in vitro studies and will define the temporal relationships of mechanically sensitive pathways involved in matrix synthesis and turnover.
Our specific aims designed to test these hypotheses are: 1. To determine the effect of two different cyclic tensile strain magnitudes (low vs. high) on collagen synthesis and MMPs 1, 3, 8 and 13 activity and gene expression in ACL fibroblasts. 2. To determine if integrin/cytoskeletal/intermediate filament/FAK, stress activated ion channels and/or SAPK/JNK signal transduction pathways are involved in mechanical regulation of collagen and MMP gene expression ACL fibroblasts. 3. To extend these in vitro studies to in vivo systems using a partial ACL transection model. The results from these studies will elucidate the molecular mechanisms involved in the mechanoregulation of matrix turnover by ACL fibroblasts and may lead to novel therapeutic approaches to the healing, reconstruction and tissue engineering of ligaments. ? ?
| Attia, Erik; Bohnert, Krista; Brown, Haydee et al. (2014) Characterization of total and active matrix metalloproteinases-1, -3, and -13 synthesized and secreted by anterior cruciate ligament fibroblasts in three-dimensional collagen gels. Tissue Eng Part A 20:171-7 |
| Wright, Vonda; Attia, Erik; Bohnert, Krista et al. (2011) Activation of MKK3/6, SAPK, and ATF-2/c-jun in ACL fibroblasts grown in 3 dimension collagen gels in response to application of cyclic strain. J Orthop Res 29:397-402 |
| Attia, Erik; Brown, Haydee; Henshaw, Ross et al. (2010) Patterns of gene expression in a rabbit partial anterior cruciate ligament transection model: the potential role of mechanical forces. Am J Sports Med 38:348-56 |
