Dissociation of Angiogenesis and Osteoclastogenesis During Endochondral Bone Formation in Neonatal Mice
作者:Martine M. L. Deckers、Ermond R. Van Beek、Gabri Van Der Pluijm、Antoinette Wetterwald、Lianne Van Der Wee-Pals、Marco G. Cecchini、Socrates E. Papapoulos、Clemens W. G. M. Löwik
DOI:10.1359/jbmr.2002.17.6.998
日期:——
Invasion of the mineralized matrix by endothelial cells and osteoclasts is a key event in endochondral bone formation. To examine the putative role of osteoclast activity in the angiogenic process, we used two in vivo models of suppressed bone resorption: mice treated with the bisphosphonate clodronate and in osteoclast‐deficient, osteopetrotic mice. Angiogenesis was assessed in caudal vertebrae of these neonatal mice. This model enables us to study the interaction between osteoclasts and endothelial cells during endochondral bone formation. In control conditions, sinusoid‐like structures were detected in the vicinity of tartrate resistance acid phosphatase positive (TRAcP+) osteoclasts. Treatment with clodronate completely abolished osteoclastic bone resorption, whereas angiogenesis remained unaffected. In line with these observations, in the osteopetrotic mouse mutants c‐fos knockout mice and op/op mice, capillaries invaded the calcified cartilage in the absence of osteoclasts. In conclusion, our data strongly suggest that during endochondral bone formation, vascular invasion can occur in the absence of osteo(chondro)clastic resorption. In addition, bisphosphonates show no apparent effect on angiogenesis in this in vivo model. These findings may have important clinical implications in the management of skeletal disorders such as metastatic bone disease, in which both osteoclastic bone resorption and angiogenesis contribute to tumor growth. On the other hand, our results confirm that bisphosphonates can be used safely in the treatment of disorders that affect the growing skeleton, such as in juvenile osteoporosis.
内皮细胞和破骨细胞侵入矿化基质是软骨内骨形成的关键过程。为了研究破骨细胞活动在血管生成过程中的推定作用,我们使用了两种抑制骨吸收的体内模型:使用双膦酸盐氯膦酸盐治疗的小鼠和破骨细胞缺陷的骨质破坏小鼠。在这些新生小鼠的尾椎骨中对血管生成进行了评估。这种模型使我们能够研究软骨内骨形成过程中破骨细胞和内皮细胞之间的相互作用。在对照条件下,酒石酸抗性酸性磷酸酶阳性(TRAcP+)破骨细胞附近可检测到窦状结构。用氯膦酸盐处理可完全抑制破骨细胞的骨吸收,而血管生成则不受影响。与这些观察结果一致的是,在骨质破坏小鼠突变体 c-fos 基因敲除小鼠和开放/开放小鼠中,在没有破骨细胞的情况下,毛细血管侵入了钙化软骨。总之,我们的数据有力地表明,在软骨内骨形成过程中,在没有破骨细胞吸收的情况下也会发生血管入侵。此外,在这种体内模型中,双膦酸盐对血管生成没有明显影响。这些发现可能对转移性骨病等骨骼疾病的治疗具有重要的临床意义,因为在转移性骨病中,破骨细胞的骨吸收和血管生成都会促进肿瘤的生长。另一方面,我们的研究结果证实,双膦酸盐可以安全地用于治疗影响骨骼生长的疾病,如青少年骨质疏松症。