Modeling extracellular matrix degradation balance with proteinase/transglutaminase cycle.

Extracellular matrix mass balance is implied in many physiological and pathological events, such as metastasis dissemination. Widely studied, its destructive part is mainly catalysed by extracellular proteinases. Conversely, the properties of the constructive part are less obvious, cellular neo-synthesis being usually considered as its only element. In this paper, we introduce the action of transglutaminase in a mathematical model for extracellular matrix remodeling. This extracellular enzyme, catalysing intermolecular protein cross-linking, is considered here as a reverse proteinase as far as the extracellular matrix physical state is concerned. The model is based on a proteinase/transglutaminase cycle interconverting insoluble matrix and soluble proteolysis fragments, with regulation of cellular proteinase expression by the fragments. Under "closed" (batch) conditions, i.e. neglecting matrix influx and fragment efflux from the system, the model is bistable, with reversible hysteresis. Extracellular matrix proteins concentration abruptly switches from low to high levels when transglutaminase activity exceeds a threshold value. Proteinase concentration usually follows the reverse complementary kinetics, but can become apparently uncoupled from extracellular matrix concentration for some parameter values. When matrix production by the cells and fragment degradation are taken into account, the dynamics change to sustained oscillations because of the emergence of a stable limit cycle. Transitions out of and into oscillation areas are controlled by the model parameters. Biological interpretation indicates that these oscillations could represent the normal homeostatic situation, whereas the other exhibited dynamics can be related to pathologies such as tumor invasion or fibrosis. These results allow to discuss the insights that the model could contribute to the comprehension of these complex biological events.