Osteoclasts are important for bone angiogenesis
Osteoclasts are important for bone angiogenesis
复制标题
DOI：
10.1182/blood-2009-08-237628
复制
发表时间：
2010-01-07
期刊：
影响因子：
20.3
通讯作者：
Roodman, G. David
中科院分区：
文献类型：
--
作者：
Cackowski, Frank C.;Anderson, Judith L.;Roodman, G. David
破骨细胞和血管生成的增加发生在生理和病理条件下。然而，目前尚不清楚这些过程是否或如何联系在一起。为了验证破骨细胞刺激血管生成的假设，我们在胎鼠跖骨外植体或成年小鼠中调节破骨细胞的形成，并测定其对血管生成的影响。骨保护素对破骨细胞形成的剂量依赖性抑制跖骨外植体血管生成和破骨细胞生成。相反，用甲状旁腺激素相关蛋白（PTHrP）治疗会增加外植体血管生成，而这一过程被骨保护素完全阻断。此外，用核因子- κ B配体受体激活剂（RANKL）或PTHrP在体内处理小鼠可增加颅骨血管密度和破骨细胞数量。接下来，我们确定基质金属蛋白酶-9 (MMP-9)，一种主要由骨破骨细胞产生的血管生成因子，是否对破骨细胞刺激的血管生成很重要。PTHrP或RANKL在Mmp9（-/-）小鼠的体内跖骨外植体或颅骨中分别没有促血管生成作用，这表明MMP-9对破骨细胞刺激的血管生成的重要性。在PTHrP或RANKL作用下，缺乏MMP-9可减少体外和体内破骨细胞数量和血管生成，但不影响体外破骨细胞分化。因此，MMP-9主要通过影响破骨细胞来调节破骨细胞刺激的血管生成，最可能是通过先前报道的对破骨细胞的迁移作用。这些结果清楚地表明，破骨细胞通过MMP-9刺激体内血管生成。(血。2010;115:140 - 149)
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 dose-dependently 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-kappa 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. 2010;115:140-149)