Abstract
Fibrosis is involved in the pathogenesis of 45% of deaths in developed countries. Thus, defining the signaling systems that promote fibrotic lesions is important for developing therapies that can preserve human health. Fibrosis affects several organs and is also commonly manifest in the gingival connective tissue of tooth-supporting tissues, which exhibit very rapid turnover of collagen. Gingiva, therefore, provides an instructive model system for determining how the signals that regulate the loss of the balance of collagen synthesis and degradation are dysregulated in gingival tissue enlargement, a common fibrotic lesion that is associated with considerable morbidity. Notably, these fibrotic lesions affect a high proportion of patients who are treated with drugs that affect Ca(2+) signaling and trafficking of collagen through vacuolar compartments. As Ca(2+) signaling is functionally related to the control of vacuolar trafficking by the small G-proteins known as Rabs, here we discuss dysregulation of collagen degradation in the gingiva with a particular focus on signaling through Rabs and on the role of vacuolar ATPases in lysosomal acidification to optimize collagen degradation. We consider how exploration of Rabs-mediated regulation of the intracellular degradation pathway may inform new approaches for the clinical management of fibrotic lesions.