Elastin peptides were previously reported to increase MMP expression in several cell types. We found binding of these peptides to their receptors led to enhanced MMP-3 and MMP-1 expression, but not activation, in human gingival fibroblasts cultured on plastic dishes. We hypothesized that these peptides, in a more physiological environment, might additionally trigger an MMP-3/MMP-1 activation cascade, leading to matrix lysis, as occurs in periodontitis. To test this hypothesis, we used contracted and attached lattices as gingival lamina propria equivalents. In such 3D models, supplementation of elastin peptides and plasminogen triggered an MMP-3/MMP-1 activation cascade and significant down-regulation of TIMPs production, further leading to intense collagen degradation. We propose that elastolysis, as occurs in periodontitis, potentiates collagenolysis, thus promoting disease progression.