Cited by 596Bone Metabolism and DiseasesProtease and Inhibitor MechanismsBone and Dental Protein Studies

Matrix Metalloproteinase 9 and Vascular Endothelial Growth Factor Are Essential for Osteoclast Recruitment into Developing Long Bones

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Engsig, Michael T., Chen, Qing-Jun, Vu, Thiennu H., Pedersen, Anne-Cecilie, Therkidsen, Bente, Lund, Leif R., Henriksen, Kim, Lenhard, Thomas +3 more·2000·The Journal of Cell Biology

Abstract

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.

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  1. Vu T. Werb Z. Gelatinase Bstructure, regulation and function Parks W.C. Mecham R.P. Matrix Metalloproteinases 1998 115 148 Academic Press San Diego.

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Authors
Engsig, M. T., Chen, Q.-J., Vu, T. H., Pedersen, A.-C., Therkidsen, B., Lund, L. R., Henriksen, K., Lenhard, T., Foged, N. T., Werb, Z., & Delaissé, J.-M.
Affiliations
  • Center for Clinical & Basic Research (DK)
  • University of California, San Francisco (US)
  • Copenhagen University Hospital (DK)
Venue
The Journal of Cell Biology
Published
2000-11-13
Volume
151
Issue
4
Pages
879-890
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
OpenAlex
W2000983409
Cited by
596
References
71
Citations by year
2026: 9 · 2025: 10 · 2024: 11 · 2023: 10 · 2022: 19 · 2021: 13 · 2020: 22 · 2019: 13 · 2018: 18 · 2017: 12 · 2016: 20 · 2015: 21 · 2014: 15 · 2013: 25 · 2012: 30
FWCI
9.53
Type
journal article
Language
en
Open access
Locations
  • The Journal of Cell Biology (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
Funders
  • Kræftens Bekæmpelse
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL03880)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR46238, R01AR046238)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
Keywords
MMP-9, vascular endothelial growth factor, osteoclast recruitment, skeletal development, long bone diaphysis, hypertrophic cartilage, chemoattraction, MMP-13, collagenase, bone resorption, capillary invasion, type I collagen
MeSH terms
Animals, Bone Development, Bone Resorption, Chemotaxis, Crosses, Genetic, Heterozygote, Lymphokines, Mice, Inbred C57BL, Osteoclasts, Protease Inhibitors, Endothelial Growth Factors, Mice, Knockout, Matrix Metalloproteinase 9, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Mice

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