Comment on: fibronectin in tissue regeneration: timely disassembly of the scaffold is necessary to complete the build

In a recent paper in Cellular and Molecular Life Sciences, Stoffels et al. [1] described, in much detail, the dual aspect of the fibronectin (Fn) matrix influence on tissue regeneration: how this protein may contribute for tissue regeneration, as a temporary scaffold for the cells, and how it can be deleterious if not properly disassembled before the entire regeneration process is completed.

Interestingly, Fn may not only influence tissue regeneration through the mechanisms described in this paper [1] but accumulated reports indicate that Fn is also able to enhance the activity of matrix metalloproteinases (MMPs) [2, 3], a set of enzymes that, among other factors, are responsible for extracellular matrix (ECM) remodeling [4]. Given that the 3D scaffold structure needs to be reabsorbed as the regeneration process takes place [1] and new EMC proteins are produced by the migrating cells, this initial surplus of MMP activity could be beneficial during the retraction of the 3D scaffold structure.

Moreover, as reported, “a variety of small proteins, such as growth factors, when they accumulate in the Fn network, increase their concentration locally” [1], and taking into consideration that MMPs may help in the bioavailability of these growth factors for tissue restoration, the enhancement of MMPs’ activity triggered by Fn accumulation may further influence the outcome of tissular regeneration, reinforcing an extra role of Fn in this process.

In a later section of the paper, the authors state that, in the case of impaired clearance of Fn, failure of the regeneration process may occur, in three different scenarios [1]. They also highlighted that non-healing cutaneous wounds presented high MMP9 activities on their respective wound fluid, which also presented Fn-degradation products [1, 5, 6]. In this sense, the permanence of these Fn products (which would have been cleared in normal healing) may trigger excessive production and/or activation of MMPs and further reinforce the authors’ hypothesis. Actually, as described, enhanced MMP activity has been seen in joints from patients who suffer from osteoarthritis, exerting direct damage on the cartilage tissue, mediated by the Fn-degradation by-products [1, 7].

In conclusion, the dual aspect of the benefits/prejudices ruled by the Fn scaffold on tissue regeneration also applies to the moderate/excessive activity of MMPs, and could further contribute to the entire understanding of the tissue repair process.