Influence of exogenous growth factors on the expression of plasminogen activators and plasminogen activator inhibitors by cells isolated from normal and healing rabbit ligaments

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Abstract
In this investigation, we demonstrate that cells from normal and healing rabbit ligaments are selective in their responsiveness to various growth factors. The cells analyzed included fibroblasts isolated from the synovium, the anterior cruciate ligament, and the medial collateral ligament (midsubstance and epiligament). Fibroblasts isolated from scar tissue of medial collateral ligament that had been allowed to heal for 3 weeks also were analyzed. The addition of insulin‐like growth factor‐2 or transforming growth factor‐β1 was observed to alter, in a dose‐dependent manner, the expression of plasminogen activator and plasminogen activator inhibitor by connective tissue cells. However, the response to these growth factors was cell specific. Fibroblasts isolated from the midsubstance, epiligament, and scar tissue of the medial collateral ligament were responsive to these growth factors; fibroblasts isolated from the anterior cruciate ligament and synovium did not have a detectable response. The cells from the normal and healing medial collateral ligament responded to both growth factors by increasing plasminogen activator inhibitor activity. This was observed at both the protein and RNA level. In contrast, the addition of insulin‐like growth factor‐1 or acidic or basic fibroblast growth factor to cells derived from normal or healing ligament did not result in any detectable alteration of plasminogen activator or plasminogen activator inhibitor activity. These results are similar to those observed with an explant system and indicate that cells isolated from ligament tissue maintain their responsiveness to these growth factors in the absence of matrix. As the major effect of insulin‐like growth factor‐2 and transforming growth factor‐β1 on the cells tested was to increase plasminogen activator inhibitor activity, such an alteration should diminish the activity of plasminogen activator, an enzyme capable of directly and indirectly proteolyzing matrix molecules, and thus contribute to a more anabolic environment.