Matrix Metalloproteinase 9 and Vascular Endothelial Growth Factor Are Essential for Osteoclast Recruitment into Developing Long Bones
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- Michael T. Engsig
- aOSTEOPRO A/S and Center for Clinical and Basic Research, DK-2750 Herlev/Ballerup, Denmark
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- Qing-Jun Chen
- aOSTEOPRO A/S and Center for Clinical and Basic Research, DK-2750 Herlev/Ballerup, Denmark
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- Thiennu H. Vu
- bDepartment of Medicine and Lung Biology Center, University of California at San Francisco, San Francisco, California 94143
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- Anne-Cecilie Pedersen
- aOSTEOPRO A/S and Center for Clinical and Basic Research, DK-2750 Herlev/Ballerup, Denmark
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- Bente Therkidsen
- aOSTEOPRO A/S and Center for Clinical and Basic Research, DK-2750 Herlev/Ballerup, Denmark
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- Leif R. Lund
- dFinsen Laboratory, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark
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- Kim Henriksen
- aOSTEOPRO A/S and Center for Clinical and Basic Research, DK-2750 Herlev/Ballerup, Denmark
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- Thomas Lenhard
- aOSTEOPRO A/S and Center for Clinical and Basic Research, DK-2750 Herlev/Ballerup, Denmark
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- Niels T. Foged
- aOSTEOPRO A/S and Center for Clinical and Basic Research, DK-2750 Herlev/Ballerup, Denmark
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- Zena Werb
- cDepartment of Anatomy, University of California at San Francisco, San Francisco, California 94143
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- Jean-Marie Delaissé
- aOSTEOPRO A/S and Center for Clinical and Basic Research, DK-2750 Herlev/Ballerup, Denmark
抄録
<jats:p>Bone development requires the recruitment of osteoclast precursors from surrounding mesenchyme, thereby allowing the key events of bone growth such as marrow cavity formation, capillary invasion, and matrix remodeling. We demonstrate that mice deficient in gelatinase B/matrix metalloproteinase (MMP)-9 exhibit a delay in osteoclast recruitment. Histological analysis and specialized invasion and bone resorption models show that MMP-9 is specifically required for the invasion of osteoclasts and endothelial cells into the discontinuously mineralized hypertrophic cartilage that fills the core of the diaphysis. However, MMPs other than MMP-9 are required for the passage of the cells through unmineralized type I collagen of the nascent bone collar, and play a role in resorption of mineralized matrix. MMP-9 stimulates the solubilization of unmineralized cartilage by MMP-13, a collagenase highly expressed in hypertrophic cartilage before osteoclast invasion. Hypertrophic cartilage also expresses vascular endothelial growth factor (VEGF), which binds to extracellular matrix and is made bioavailable by MMP-9 (Bergers, G., R. Brekken, G. McMahon, T.H. Vu, T. Itoh, K. Tamaki, K. Tanzawa, P. Thorpe, S. Itohara, Z. Werb, and D. Hanahan. 2000. Nat. Cell Biol. 2:737–744). We show that VEGF is a chemoattractant for osteoclasts. Moreover, invasion of osteoclasts into the hypertrophic cartilage requires VEGF because it is inhibited by blocking VEGF function. These observations identify specific actions of MMP-9 and VEGF that are critical for early bone development.</jats:p>
収録刊行物
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- The Journal of Cell Biology
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The Journal of Cell Biology 151 (4), 879-890, 2000-11-13
Rockefeller University Press