The integrin-mediated stress relaxation as it occurs in a retracting three-dimensional collagen gel (RCG) is accompanied by a large up-regulation of the interstitial collagenase, matrix metalloproteinase 1 ((MMP Integrins are transmembrane heterodimeric proteins providing a structural link between the extracellular matrix and the cytoskeleton. They are responsible for the transduction to the cell of information arising from specific sequences within the macromolecules and/or triggered by the mechanical properties of their polymers. Both messages, chemical and/or mechanical, are responsible for controlling signaling processes that involve assembly of multiple proteins in the focal adhesion plaque, organization of cytoskeletal actin polymers, and their anchorage to the cell membrane, protein phosphorylation and activation of signaling cascades leading to regulation of genes expression through several potential pathways (1). The interactions of cells with the extracellular matrix are essential in many biological and pathophysiological processes as embryonic development, wound healing, fibrosis, tumor invasion, and metastasis.-Most of the integrin-mediated regulations and signaling by mechanical forces have been investigated in cells under stress (1, 2). Much less is known about the messages that the cells receive and the signaling that is triggered when stress is released. This event is relevant to investigate since it participates in physiological and pathological processes observed during extracellular matrix degradation in remodeling, cancer and inflammatory diseases, mammary epithelium differentiation (3), and osteoporosis induced by suppression of muscular activity or in weightlessness conditions (4). Furthermore, reduced mechanical tension is actually regarded as a signal inducing programmed cell death (5, 6)The culture of cells within a free floating gel of collagen polymers offers a model of integrin-mediated stress relaxation. When fibroblasts are cultured in such a gel, they attach to the fibers and retract the gel. According to the "tensegrity" concept proposed by Ingber (7), the dissipation of mechanical tension upon retraction of the malleable collagen gel results in alteration of the dynamic balance of the cytoskeleton. It is visualized by the reorganization of the actin network with the disappearance of the stress fibers (8) and the assembly of actin clusters along the cell periphery (9). This process is accompanied by a profound reprogramming of the cell phenotype. We, and others, have demonstrated an arrest of cell division, an extensive reduction of collagen and other structural macromolecules expression (10, 11), whereas a large up-regulation of interstitial collagenase (MMP-1, 1 EC 3.4.24.7) was observed (12, 13). It was recently demonstrated that ␣ 2  1 is the major determinant of the contraction of the collagen gel (14, 15) and the mediator of the regulation of the MMP-1 gene in fibroblasts cultured in a retracting collagen gel while ␣ 1  1 mediates the COL1A1 gene down-regulation (16,17).MM...