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

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.

• Publication year

  2000

• Venue

  Journal of Cell Biology

• Publication date

  2000-11-13

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1083/JCB.151.4.879PMID 11076971PMCID 2169432
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• MMP-9 promotes the solubilization of unmineralized cartilage by MMP-13.

  Confidence 0.90

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• VEGF acts as a chemoattractant for osteoclasts and is required for their invasion of hypertrophic cartilage.

  Confidence 0.95

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• MMP-9 is required for osteoclast recruitment into developing long bones, especially for invasion into hypertrophic cartilage.

  Confidence 0.98

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review

• developing long bones

  anatomical structure, developmental context

  Immature long bones undergoing marrow cavity formation, vascular invasion, and matrix remodeling.

  Aliases: developing bone, long bone development

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• hypertrophic cartilage

  tissue, cartilage

  The mineralizing cartilage tissue in the growth plate region that fills the core of the developing diaphysis.

  Aliases: hypertrophic cartilage core

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• mmp-13

  enzyme, protein

  A collagenase expressed in hypertrophic cartilage and implicated here in cartilage matrix solubilization.

  Aliases: matrix metalloproteinase 13

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• mmp-9

  enzyme, protein

  A gelatinase matrix metalloproteinase studied here for its role in cell invasion during bone development.

  Aliases: gelatinase B, matrix metalloproteinase 9

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• osteoclast recruitment

  biological process, cellular process

  The process by which osteoclast precursors and osteoclasts are attracted into developing bone tissues.

  Aliases: osteoclast invasion

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• vegf

  growth factor, protein

  A vascular growth factor associated here with matrix-bound signaling and chemoattraction during bone development.

  Aliases: vascular endothelial growth factor

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review

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