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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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Effect of MMP-9 deficiency on the resorption of different types of bones. Calvariae of E18 embryos and tibiae and metatarsals of E17 embryos were obtained from two and eight litters, respectively, of heterozygote parents. The embryos were phenotyped as MMP-9–positive (circles) or MMP-9–negative (triangles). The bone explants were cultured for the indicated times. Each point shows the mean ± SD of 45Ca release determined in independent cultures of 41 MMP-9–positive and 23 MMP-9–negative metatarsals or tibiae, or 9 MMP-9–positive and 4 MMP-9–negative calvariae. Significant differences in 45Ca release from MMP-9–positive and MMP-9–negative explants were seen only for the metatarsals (P < 0.05).
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Figure 1: Effect of MMP-9 deficiency on the resorption of different types of bones. Calvariae of E18 embryos and tibiae and metatarsals of E17 embryos were obtained from two and eight litters, respectively, of heterozygote parents. The embryos were phenotyped as MMP-9–positive (circles) or MMP-9–negative (triangles). The bone explants were cultured for the indicated times. Each point shows the mean ± SD of 45Ca release determined in independent cultures of 41 MMP-9–positive and 23 MMP-9–negative metatarsals or tibiae, or 9 MMP-9–positive and 4 MMP-9–negative calvariae. Significant differences in 45Ca release from MMP-9–positive and MMP-9–negative explants were seen only for the metatarsals (P < 0.05).

Mentions: MMPs are rate-limiting for bone resorption in cultures of embryonic day (E)18 calvariae and E17 tibiae which are rich in mature bone–resorbing osteoclasts and in cultures of E17 metatarsals that lack mature osteoclasts, but depend on recruitment of (pre)osteoclasts for resorption (Delaissé et al. 1985; Hill et al. 1994; Blavier and Delaissé 1995; Everts et al. 1998). Osteoclasts and osteoclast precursors express MMP-9 at a high level (Reponen et al. 1994; Tezuka et al. 1994; Blavier and Delaissé 1995; Okada et al. 1995). Therefore, we used MMP-9−/− mice to investigate the effect of MMP-9 deficiency in these calvaria, tibia, and metatarsal bone resorption models (Fig. 1). The absence of MMP-9 did not affect the demineralization rates of the calvariae and tibiae, but did reduce demineralization of metatarsals to 30% of the values found in the MMP-9–positive controls. These data suggest that MMP-9 deficiency affects resorption of calcified skeletal elements only in situations where osteoclast recruitment is a prerequisite for resorption.


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 the resorption of different types of bones. Calvariae of E18 embryos and tibiae and metatarsals of E17 embryos were obtained from two and eight litters, respectively, of heterozygote parents. The embryos were phenotyped as MMP-9–positive (circles) or MMP-9–negative (triangles). The bone explants were cultured for the indicated times. Each point shows the mean ± SD of 45Ca release determined in independent cultures of 41 MMP-9–positive and 23 MMP-9–negative metatarsals or tibiae, or 9 MMP-9–positive and 4 MMP-9–negative calvariae. Significant differences in 45Ca release from MMP-9–positive and MMP-9–negative explants were seen only for the metatarsals (P < 0.05).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Effect of MMP-9 deficiency on the resorption of different types of bones. Calvariae of E18 embryos and tibiae and metatarsals of E17 embryos were obtained from two and eight litters, respectively, of heterozygote parents. The embryos were phenotyped as MMP-9–positive (circles) or MMP-9–negative (triangles). The bone explants were cultured for the indicated times. Each point shows the mean ± SD of 45Ca release determined in independent cultures of 41 MMP-9–positive and 23 MMP-9–negative metatarsals or tibiae, or 9 MMP-9–positive and 4 MMP-9–negative calvariae. Significant differences in 45Ca release from MMP-9–positive and MMP-9–negative explants were seen only for the metatarsals (P < 0.05).
Mentions: MMPs are rate-limiting for bone resorption in cultures of embryonic day (E)18 calvariae and E17 tibiae which are rich in mature bone–resorbing osteoclasts and in cultures of E17 metatarsals that lack mature osteoclasts, but depend on recruitment of (pre)osteoclasts for resorption (Delaissé et al. 1985; Hill et al. 1994; Blavier and Delaissé 1995; Everts et al. 1998). Osteoclasts and osteoclast precursors express MMP-9 at a high level (Reponen et al. 1994; Tezuka et al. 1994; Blavier and Delaissé 1995; Okada et al. 1995). Therefore, we used MMP-9−/− mice to investigate the effect of MMP-9 deficiency in these calvaria, tibia, and metatarsal bone resorption models (Fig. 1). The absence of MMP-9 did not affect the demineralization rates of the calvariae and tibiae, but did reduce demineralization of metatarsals to 30% of the values found in the MMP-9–positive controls. These data suggest that MMP-9 deficiency affects resorption of calcified skeletal elements only in situations where osteoclast recruitment is a prerequisite for resorption.

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