Matrix Metalloproteinase 9 and Vascular Endothelial Growth Factor Are Essential for Osteoclast Recruitment into Developing Long Bones
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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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MMP-9-knockout mice showed reduced osteoclast invasion into the core of developing bones, and in vitro osteoclasts lacking MMP9 did not migrate.
“MMP-9-KO mice showed reduced osteoclast invasion into the core of developing bones,151 and in vitro, osteoclasts lacking MMP9 did not migrate.152”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [151]
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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
- Publisher
- Rockefeller University Press
- Published
- 2000-11-13
- Volume
- 151
- Issue
- 4
- Pages
- 879-890
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2169432
- 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
- bronze
- doi.org
- 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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