Osteoclasts are important for bone angiogenesis

Abstract

Increased osteoclastogenesis and angiogenesis occur in physiologic and pathologic conditions. However, it is unclear if or how these processes are linked. To test the hypothesis that osteoclasts stimulate angiogenesis, we modulated osteoclast formation in fetal mouse metatarsal explants or in adult mice and determined the effect on angiogenesis. Suppression of osteoclast formation with osteoprotegerin dosedependently inhibited angiogenesis and osteoclastogenesis in metatarsal explants. Conversely, treatment with parathyroid hormone related protein (PTHrP) increased explant angiogenesis, which was completely blocked by osteoprotegerin. Further, treatment of mice with receptor activator of nuclear factor-B ligand (RANKL) or PTHrP in vivo increased calvarial vessel density and osteoclast number. We next determined whether matrix metalloproteinase-9 (MMP-9), an angiogenic factor predominantly produced by osteoclasts in bone, was important for osteoclast-stimulated angiogenesis. The pro-angiogenic effects of PTHrP or RANKL were absent in metatarsal explants or calvaria in vivo, respectively, from Mmp9 ؊/؊ mice, demonstrating the importance of MMP-9 for osteoclast-stimulated angiogenesis. Lack of MMP-9 decreased osteoclast numbers and abrogated angiogenesis in response to PTHrP or RANKL in explants and in vivo but did not decrease osteoclast differentiation in vitro. Thus, MMP-9 modulates osteoclast-stimulated angiogenesis primarily by affecting osteoclasts, most probably by previously reported migratory effects on osteoclasts. These results clearly demonstrate that osteoclasts stimulate angiogenesis in vivo through MMP-9. (Blood.

High Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiation

“…Similarly, the expression of DC-STAMP (dendritic cell-specific transmembrane protein) and Atp6v0d2 (d2 isoform of vacuolar ATPase V o domain), NFATc1 targets that participate in osteoclast fusion, was also reduced. Matrix metalloproteinase 9 and CD44, which are involved in osteoclast migration and fusion (31)(32)(33), were also decreased in Cx37-deficient cultures. On the other hand, either other molecules associated with osteoclast function were not changed (osteoclast-associated receptor, OSCAR), or their decrease did not reach significance (integrin ␤3 and E-cadherin).…”

Erythropoietin Modulates the Structure of Bone Morphogenetic Protein 2–Engineered Cranial Bone

“…33 Briefly, metatarsals were dissected from *17-day embryos (C57BL/6; Harlan) and cultured in 24-well plates containing 150 mL aminimum essential medium (Invitrogen) and 10% FBS (Invitrogen) for the first 3 days. The medium was replaced by 250 mL fresh medium containing vascular endothelial growth factor (VEGF, 10 ng/mL; PeproTech), Epo (10 U/mL; Amgen), BMP2 (10 ng/mL; PeproTech), alendronate (10 nM, ALN; Calbiochem), or osteoprotegerin (1 mg/mL OPG; R&D Systems, Inc.) on fourth day.…”

“…These data may also explain why the more potent angiogenic effects of Epo were observed in the metatarsal bone model (organ culture including osteoclastogenesis) rather than in the endothelial tube formation model (HUVECs without osteoclasts) and is supported by the recent report on the novel role of osteoclasts for bone angiogenesis. 33 Although Epo increased osteoclastogenesis and angiogenesis and thus improved BMP2-induced bone regeneration, the mechanism by which Epo changed the ratio of BMP2-generated bone and marrow is not clear. Cranial bone is normally repaired through the intramembranous bone formation pathway, as it is in normal development.…”

Angiogenesis and Multiple Myeloma

“…OPN is secreted by osteoclasts in the myeloma microenvironment [76], suggesting that these cells may contribute to the angiogenic activity of this factor in MM. Interestingly, recent data suggest that osteoclasts act as angiogenic cells and regulate angiogenesis in the BM [77].…”