Limits...
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.

Show MeSH

Related in: MedlinePlus

Effect of MMP-9 deficiency on number of nuclei per TRAP+ cell. The number of nuclei per TRAP+ cell were calculated from the counts of cells and nuclei shown in Fig. 5, and are shown as mean ± SD.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2169432&req=5

Figure 6: Effect of MMP-9 deficiency on number of nuclei per TRAP+ cell. The number of nuclei per TRAP+ cell were calculated from the counts of cells and nuclei shown in Fig. 5, and are shown as mean ± SD.

Mentions: MMP-9−/− bones from embryos of the same litter and of the same age differed from these MMP-9+/− bones mainly in two respects. First, the increase in the number of nuclei of TRAP+ cells was only 70% of that of MMP-9+/− bones (Fig. 5). The average number of nuclei per osteoclast, however, was not affected (Fig. 6). This observation suggests that the lack of MMP-9 does not affect cell fusion. Second, and more importantly, MMP-9 deficiency resulted in a delayed invasion of TRAP+ cells into the calcified cartilage (Fig. 5 and Fig. 7). At E18 and E19, the proportions of nuclei in the calcified cartilage were 20 and 40%, respectively, of those in MMP-9–positive bones. The osteoclasts of the MMP-9–negative bones tended then to accumulate at the interface between the osteoid (i.e., unmineralized collagen) of the bone collar and the calcified cartilage. During this period, the distribution of endothelial cells inside and outside the calcified cartilage was closely coordinated with that of TRAP+ cells, whether MMP-9 was lacking or not. Endothelial cells appeared inside the calcified cartilage only when TRAP+ cells had invaded the calcified cartilage (Fig. 7). Thus, the main result of MMP-9 deficiency was an impaired migration of TRAP+ cells and endothelial cells from the periosteum to the calcified cartilage.


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)

Effect of MMP-9 deficiency on number of nuclei per TRAP+ cell. The number of nuclei per TRAP+ cell were calculated from the counts of cells and nuclei shown in Fig. 5, and are shown as mean ± SD.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: Effect of MMP-9 deficiency on number of nuclei per TRAP+ cell. The number of nuclei per TRAP+ cell were calculated from the counts of cells and nuclei shown in Fig. 5, and are shown as mean ± SD.
Mentions: MMP-9−/− bones from embryos of the same litter and of the same age differed from these MMP-9+/− bones mainly in two respects. First, the increase in the number of nuclei of TRAP+ cells was only 70% of that of MMP-9+/− bones (Fig. 5). The average number of nuclei per osteoclast, however, was not affected (Fig. 6). This observation suggests that the lack of MMP-9 does not affect cell fusion. Second, and more importantly, MMP-9 deficiency resulted in a delayed invasion of TRAP+ cells into the calcified cartilage (Fig. 5 and Fig. 7). At E18 and E19, the proportions of nuclei in the calcified cartilage were 20 and 40%, respectively, of those in MMP-9–positive bones. The osteoclasts of the MMP-9–negative bones tended then to accumulate at the interface between the osteoid (i.e., unmineralized collagen) of the bone collar and the calcified cartilage. During this period, the distribution of endothelial cells inside and outside the calcified cartilage was closely coordinated with that of TRAP+ cells, whether MMP-9 was lacking or not. Endothelial cells appeared inside the calcified cartilage only when TRAP+ cells had invaded the calcified cartilage (Fig. 7). Thus, the main result of MMP-9 deficiency was an impaired migration of TRAP+ cells and endothelial cells from the periosteum to the calcified cartilage.

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