Matrix-metalloproteinase-14 deficiency in bone-marrow-derived cells promotes collagen accumulation in mouse atherosclerotic plaques.

Abstract

Interstitial collagen plays a crucial structural role in arteries. Although in vitro results suggest collagenase activity for membrane-bound matrix metalloproteinase type 1 (MMP-14), in vivo evidence for such a function in atherosclerosis remains scant. Because Mmp14-/- mice die by 3 weeks of age, this study used lethally irradiated low-density lipoprotein receptor-deficient mice reconstituted with syngeneic bone marrow cells of Mmp14-/- or Mmp14+/+ mice. In both groups, histological analyses of the aortic root revealed similar plaque size and macrophage and smooth muscle cell content after 8 or 16 weeks of atherogenic diet. By 16 weeks, however, the plaques of low-density lipoprotein receptor-deficient mice engrafted with Mmp14-/- bone marrow (n=12) contained significantly more interstitial collagen than those receiving Mmp14+/+ bone marrow (n=14; P<0.05). In vitro, bone marrow-derived macrophages from Mmp14-/- mice had significantly less interstitial collagenase activity than those from Mmp14+/+ mice both basally (P<0.01) and on tumor necrosis factor-alpha stimulation (P<0.05). Western blot analysis and gelatin zymography of aortic extracts revealed that MMP-14 deficiency yielded decreased activation of pro-MMP-13 but not of pro-MMP-2 or pro-MMP-8. MMP-14 from bone marrow-derived cells can influence the collagen content of mouse atheroma, a critical component of plaque stability.