Level II, prospective comparative study.

Partial or complete surgical transection of the rabbit ACL with resultant loss of mechanical stimuli results in an increase in MMP-13 and alpha-SMA expression at the early time point (1 week) and an increase in alpha-SMA, Col I, and Col III expression at the later time point (6 weeks). These data provide support for the hypothesis that there is a time-dependent alteration of anabolic and catabolic matrix gene expression after injury/loss of ligament integrity. Clinical Relevance Identification of pathways that respond to mechanical stress in the intact ACL and after surgical transection may permit development of novel therapies to alter healing of the partial ACL injury or to assist in the development of biomechanical active ''smart'' scaffolds for tissue-engineered ligament replacements.

No abstract

It is difficult to predict outcomes after CSI. Our treatment strategy showed a 40% failure rate.

Signal transduction pathways involved in response to cyclic tensile strain and strain deprivation in anterior cruciate ligament (ACL) fibroblasts grown in 3D collagen gels were investigated. Application of cyclic tensile strain resulted in significant activation (phosphorylation) of MKK3/6, SAPK and their downstream target transcription factors, ATF-2 and c-jun, while strain deprivation resulted in a decrease in these kinases and transcription factors. These data suggest that ACL fibroblasts cultured in 3D collagen gels respond to the mechanical environment and provide a useful system for determination of the molecular mechanisms involved in the regulation of proliferation and matrix turnover by mechanical load. Mechanical stimulus is vital for optimal maintenance of ligament and tendon 1,2 with fibroblast proliferation and matrix turnover playing critical roles in the mechano-regulation of the structure and function of ligaments. Previous studies have shown that cyclic strain modulates cell proliferation, growth arrest, 3-5 matrix synthesis, 6-15 and matrix metalloproteinase (MMP) content and activity 12,16-18 in a wide variety of cell types. The mechanisms by which the cells convert a mechanical signal into a biochemical response are not well understood, although integrins are key mechanosensors. 19,20 This study was designed to test the hypothesis that cjun and ATF-2 are activated in response to cyclic tensile strain via stress activated protein kinase (Fig. 1).Although important information has been obtained from the studies cited above, the majority were performed in monolayer cell culture. The availability of three dimensional collagen gels for the culture of ligament cells 21 in vitro provides an opportunity to apply tensile mechanical strain utilizing a more physiologic 3D cell-matrix construct. Tethered and loaded gels maintain a linear structure, while released gels contract significantly resulting in an amorphous structure. We have previously shown that the fibroblasts within the gels and intracellular actin filaments align along the long axis of the gel within 24 h. This alignment is lost in released gels, with cells becoming randomly distributed and showing disorganized actin and collagen orientation. 21 This model permits the investigation of signaling pathways involved in regulation of cell proliferation and matrix turnover. We hypothesized that application of