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


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-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.


CONCLUSIONS
MMP-14 from bone marrow-derived cells can influence the collagen content of mouse atheroma, a critical component of plaque stability.
Schneider
Fabrice
F
Donald W. Reynolds Cardiovascular Clinical Research Center and Fondation Leducq Transatlantic Network on Atherothrombosis, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA.
Sukhova
Galina K
GK
Aikawa
Masanori
M
Canner
James
J
Gerdes
Norbert
N
Tang
Sai-Man Timothy
SM
Shi
Guo-Ping
GP
Apte
Suneel S
SS
Libby
Peter
P
D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001854:Bone Marrow Cells / Q000201:enzymology*; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000378:metabolism*; D004036:Diet, Atherogenic; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology; D008264:Macrophages / Q000201:enzymology; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D018919:Neovascularization, Physiologic; D011828:Radiation Chimera; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004792:Enzyme Precursors; C507096:Mmp14 protein, mouse; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D002784:Cholesterol; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D053511:Matrix Metalloproteinase 14