Diffusion of MMPs on the Surface of Collagen Fibrils: The Mobile Cell Surface – Collagen Substratum Interface

Remodeling of the extracellular matrix catalyzed by MMPs is central to morphogenetic phenomena during development and wound healing as well as in numerous pathologic conditions such as fibrosis and cancer. We have previously demonstrated that secreted MMP-2 is tethered to the cell surface and activated by MT1-MMP/TIMP-2-dependent mechanism. The resulting cell-surface collagenolytic complex (MT1-MMP)2/TIMP-2/MMP-2 can initiate (MT1-MMP) and complete (MMP-2) degradation of an underlying collagen fibril. The following question remained: What is the mechanism of substrate recognition involving the two structures of relatively restricted mobility, the cell surface enzymatic complex and a collagen fibril embedded in the ECM? Here we demonstrate that all the components of the complex are capable of processive movement on a surface of the collagen fibril. The mechanism of MT1-MMP movement is a biased diffusion with the bias component dependent on the proteolysis of its substrate, not adenosine triphosphate (ATP) hydrolysis. It is similar to that of the MMP-1 Brownian ratchet we described earlier. In addition, both MMP-2 and MMP-9 as well as their respective complexes with TIMP-1 and -2 are capable of Brownian diffusion on the surface of native collagen fibrils without noticeable dissociation while the dimerization of MMP-9 renders the enzyme immobile. Most instructive is the finding that the inactivation of the enzymatic activity of MT1-MMP has a detectable negative effect on the cell force developed in miniaturized 3D tissue constructs. We propose that the collagenolytic complex (MT1-MMP)2/TIMP-2/MMP-2 represents a Mobile Cell Surface – Collagen Substratum Interface. The biological implications of MT1-MMP acting as a molecular ratchet tethered to the cell surface in complex with MMP-2 suggest a new mechanism for the role of spatially regulated peri-cellular proteolysis in cell-matrix interactions

Revisiting diffusion models: portuguese integrated management Systems evolution

This paper aims to update and report the diffusion and forecasting models of Portuguese integrated management systems (IMSs) encompassing the ISO 9001, ISO 14001 and OHSAS 18001 standards (QES). A research method similar to that described by Cabecinhas et al. [1] was adopted. Data concerning the evolution of the amount of multiple MSs in Portugal (ranging from 1999 to 2016) was retrieved from a periodical Portuguese publication (Barómetro da Certificação). The evolutionary behavior of the number of MSs over the years was studied adopting both the Gompertz and the Simple Logistic models. The results obtained by fitting the data to these models were dissected enabling a forecast for the forthcoming years. In opposition to the results of the original study (based on a higher percentage of extrapolated data) the data seem to be properly fitted by the Simple Logistic model. Similarly to the conclusions of the original study the diffusion throughout the years of the number of MSs presents an S-shaped behavior and the Gompertz model predicts a higher amount of IMSs at the saturation level (which is in line with the original conclusions).The authors would like to thank the collaboration of several certification entities. This work has been supported by FCT – Fundação para a Ciência e Tecnologia within the Project Scope: UID/CEC/00319/2019. Mónica Cabecinhas is supported by FCT Doctorate Grant Reference SFRH/BD/131932/2017. Pedro Domingues is supported by FCT Post-Doc Grant Reference SFRH/BPD/103322/2014