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Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones.

Engsig MT, Chen QJ, Vu TH, Pedersen AC, Therkidsen B, Lund LR, Henriksen K, Lenhard T, Foged NT, Werb Z, Delaissé JM - J. Cell Biol. (2000)

Bottom Line: Hanahan. 2000.Cell Biol. 2:737-744).These observations identify specific actions of MMP-9 and VEGF that are critical for early bone development.

View Article: PubMed Central - PubMed

Affiliation: OSTEOPRO A/S and Center for Clinical and Basic Research, DK-2750 Herlev/Ballerup, Denmark. me@osteopro.dk

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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Comparative effect of MMP-9 deficiency and of a general MMP inhibitor on osteoclast migration through type I collagen. Osteoclasts of MMP-9–positive and MMP-9–negative mice were cultured on collagen-coated filters in the presence and absence of 10 μM GM6001 (average of 227 osteoclasts/filter). Their invasion through the collagen was evaluated as explained in Materials and Methods, and is shown as means ± SD of three cultures. *Significant effect compared with osteoclasts of MMP-9–positive mice cultured without inhibitor (P < 0.05).
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Figure 8: Comparative effect of MMP-9 deficiency and of a general MMP inhibitor on osteoclast migration through type I collagen. Osteoclasts of MMP-9–positive and MMP-9–negative mice were cultured on collagen-coated filters in the presence and absence of 10 μM GM6001 (average of 227 osteoclasts/filter). Their invasion through the collagen was evaluated as explained in Materials and Methods, and is shown as means ± SD of three cultures. *Significant effect compared with osteoclasts of MMP-9–positive mice cultured without inhibitor (P < 0.05).

Mentions: When the TRAP+ cells migrate from the periosteum to the calcified cartilage, they must overcome a barrier of unmineralized bone matrix, called osteoid, that comprises mainly type I collagen (Blavier and Delaissé 1995). Migration of osteoclasts through type I collagen is inhibited by a general MMP inhibitor (Sato et al. 1998). To evaluate whether MMP-9 is critical for migration of osteoclasts through collagen, we compared migration rates of MMP-9–positive and MMP-9–negative osteoclasts through collagen-coated membranes. A general MMP inhibitor strongly blocked invasion of both phenotypes to the same extent. However, MMP-9−/− osteoclasts were not significantly less invasive (Fig. 8). These data indicate that a metalloproteinase (or metalloproteinases) different from MMP-9 is critical for the invasive activity of osteoclasts into collagen.


Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones.

Engsig MT, Chen QJ, Vu TH, Pedersen AC, Therkidsen B, Lund LR, Henriksen K, Lenhard T, Foged NT, Werb Z, Delaissé JM - J. Cell Biol. (2000)

Comparative effect of MMP-9 deficiency and of a general MMP inhibitor on osteoclast migration through type I collagen. Osteoclasts of MMP-9–positive and MMP-9–negative mice were cultured on collagen-coated filters in the presence and absence of 10 μM GM6001 (average of 227 osteoclasts/filter). Their invasion through the collagen was evaluated as explained in Materials and Methods, and is shown as means ± SD of three cultures. *Significant effect compared with osteoclasts of MMP-9–positive mice cultured without inhibitor (P < 0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2169432&req=5

Figure 8: Comparative effect of MMP-9 deficiency and of a general MMP inhibitor on osteoclast migration through type I collagen. Osteoclasts of MMP-9–positive and MMP-9–negative mice were cultured on collagen-coated filters in the presence and absence of 10 μM GM6001 (average of 227 osteoclasts/filter). Their invasion through the collagen was evaluated as explained in Materials and Methods, and is shown as means ± SD of three cultures. *Significant effect compared with osteoclasts of MMP-9–positive mice cultured without inhibitor (P < 0.05).
Mentions: When the TRAP+ cells migrate from the periosteum to the calcified cartilage, they must overcome a barrier of unmineralized bone matrix, called osteoid, that comprises mainly type I collagen (Blavier and Delaissé 1995). Migration of osteoclasts through type I collagen is inhibited by a general MMP inhibitor (Sato et al. 1998). To evaluate whether MMP-9 is critical for migration of osteoclasts through collagen, we compared migration rates of MMP-9–positive and MMP-9–negative osteoclasts through collagen-coated membranes. A general MMP inhibitor strongly blocked invasion of both phenotypes to the same extent. However, MMP-9−/− osteoclasts were not significantly less invasive (Fig. 8). These data indicate that a metalloproteinase (or metalloproteinases) different from MMP-9 is critical for the invasive activity of osteoclasts into collagen.

Bottom Line: Hanahan. 2000.Cell Biol. 2:737-744).These observations identify specific actions of MMP-9 and VEGF that are critical for early bone development.

View Article: PubMed Central - PubMed

Affiliation: OSTEOPRO A/S and Center for Clinical and Basic Research, DK-2750 Herlev/Ballerup, Denmark. me@osteopro.dk

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.

Show MeSH
Related in: MedlinePlus