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

By M. Engsig, Qing-Jun Chen, Thiennu H. Vu, A. Pedersen, Bente Therkidsen, L. Lund, K. Henriksen, T. Lenhard, N. Foged, Zena Werb and 1 more. Journal of Cell Biology, 2000

617 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/43c5e3a89cdb6152c2e0f16f069f5f6442fe8615

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. P. E. Van den Steen
2. G. Opdenakker
3. Zena Werb
4. D. Lyden
5. Shahin Rafii
6. E. Wagner
7. T. Klein
8. Rainer Bischoff

In Molecular Biology

1. Shahin Rafii
2. D. Lyden
3. Zena Werb
4. E. Wagner
5. J. Kanczler
6. G. Opdenakker
7. G. Karsenty
8. P. E. Van den Steen

In Rheumatology

1. T. Klein
2. Rainer Bischoff

Citations in the corpus

• Physiology and pathophysiology of matrix metalloproteases (2010, background): “1998) and reduced osteoclast recruitment (Engsig et al. 2000).”
• How matrix metalloproteinases regulate cell behavior. (2001, background): “In addition, mFlt-IgG inhibits the recruitment of chondroclasts, osteoblasts and osteoclasts (Gerber et al. 1999, Engsig et al. 2000).”
• Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9) (2002, background): “Furthermore, VEGF is chemotactic for osteoclasts that can release gelatinase B (Engsig et al., 2000).”
• Osteogenesis and angiogenesis: the potential for engineering bone. (2008, background): “VEGF and matrix metalloproteinase-9 (MMP-9) are critical for early bone development (Engsig et al., 2000).”
• Reaching a genetic and molecular understanding of skeletal development. (2002, background): “…see the same confluence of the Wnt, FGF, and BMP signaling pathways in the specification of joint forma- junction and by the fact that they express more MMP9 but less Trap than do osteoclasts (Engsig et al., 2000;tion, as is seen in other developmental events (Wilson et al., 2001).”
• Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. (2002, background): “…the microen- and Increased Mortality after Myeloablation What is the role of increased sKitL levels in the contextvironment of developing bone (Engsig et al., 2000) or within tumors of pancreatic islets (Bergers et al., 2000). of hematopoietic recovery after BM suppression or stem cell…”
• Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development (2003, background): “Recruitment of MMP9-expressing chondroclasts/osteoclasts to the growth plate is dependent on VEGF (Engsig et al., 2000).”