Matrix Metalloproteinase-14 Deficiency in Bone Marrow–Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques

Abstract

Background— 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. Methods and Results— 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-α 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. Conclusion— MMP-14 from bone marrow–derived cells can influence the collagen content of mouse atheroma, a critical component of plaque stability.