The plasminogen activator and inhibitor system in bone remodelling

The neutral protease, plasmin, is generated by plasminogen activators, and is ascribed an important role in several physiological and pathological circumstances characterized by tissue remodelling and cell motility. The two types of plasminogen activator, tissue-type (tPA) and urokinase-type (uPA), are produced by osteoblasts, as is the specific PA inhibitor, PAI-1. Some hormones which activate bone resorption increase PA activity produced by osteoblasts, by decreasing the production of PAI-1. The increased PA activity has been suggested to facilitate bone resorption by activating latent collagenase, thus preparing the bone surface for osteoclastic resorption. Targeted and regulated production of plasmin might also contribute to the coupling of bone formation to resorption, by activating latent TGF beta in bone, and activating IGF-1 by freeing it from association with inhibitory binding protein. TGF beta itself is a powerful inhibitor of PA activity, an effect achieved by enhancing mRNA and protein for PAI-1. Thus the PA system is a potentially important regulatory system in bone remodelling, whose local activity is controlled through concerted actions of hormones and locally generated growth factors and cytokines.