Site-specific tissue inhibitor of metalloproteinase-1 governs the matrix metalloproteinases-dependent degradation of crosslinked collagen scaffolds and is correlated with interleukin-10.

We have previously shown that the foreign body reaction (FBR) against crosslinked collagen type I (Col-I) differs between subcutaneous and epicardial implantation sites; Col-I was quickly degraded epicardially, whereas degradation was attenuated subcutaneously. The current study set out to dissect the nature and regulation of the MMP-based degradation of implanted Col-I in mice during the FBR. Immunohistochemistry showed that MMP-2, MMP-8 and MMP-13 were present in subcutaneous and epicardial implants, whereas only MMP-9 was also present epicardially. Western blotting showed that MMP-8 and MMP-9 were mainly present in their inactive proform. In contrast, collagenase MMP-13 and gelatinase MMP-2 were the predominant active MMPs at both sites. Interestingly, the major MMP inhibitor TIMP-1 was solely observed in subcutaneous implants, which is why MMP-13 and MMP-2 are not able to degrade the collagen scaffold at the subcutaneous implantation site. Interleukin 10 (IL-10), a potent inducer of TIMP-1 expression, was also mainly detected subcutaneously; giant cells were the main source. Therefore, we surmise that IL-10, through regulation of the balance between MMPs and TIMP-1, suppresses the FBR against implanted biomaterials. Together, our findings would provide cues and clues to improve future therapies in regenerative medicine that are based on the tuned regulation of the degradation of biomaterial scaffolds.