Published Online
on February 4, 2008

A more recent version of this article appeared on February 19, 2008

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Submitted on April 29, 2007
Accepted on November 27, 2007

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

Fabrice Schneider MD, Galina K. Sukhova PhD, Masanori Aikawa MD, PhD, James Canner MA, Norbert Gerdes PhD, Sai-Man Timothy Tang Bsc, Guo-Ping Shi DSc, Suneel S. Apte MBBS, DPhil, and Peter Libby MD^*

From the Donald W. Reynolds Cardiovascular Clinical Research Center and Fondation Leducq Transatlantic Network on Atherothrombosis (F.S., G.K.S., M.A., J.C., N.G., S.-M.T.T., G.-P.S., P.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Service de Chirurgie Vasculaire (F.S.), Hôpital Henri Mondor, Créteil, France; Department of Biomedical Engineering (S.S.A.), Lerner Research Institute Cleveland Clinic, Cleveland, Ohio; and Center for Molecular Medicine (N.G.), Karolinska Institute, Stockholm, Sweden.

^* To whom correspondence should be addressed. E-mail: plibby{at}rics.bwh.harvard.edu.

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- 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.

Key words: atherosclerosis • collagen • metalloproteinases • pathology • plaque

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Clinical Summaries
Circulation 2008 117: 857-859. [Extract] [Full Text]

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