STUDIES OF THE FATE OF THE OSTEOCLAST

破骨细胞是软骨内骨化过程中骨正常发育和正常骨重建过程中成人骨骼中磨损骨再吸收所必需的。它们还介导与绝经后骨炎症和雌激素缺乏相关的骨丢失增加。最近的研究表明，M-CSF和RANK（NF-κ B受体活化）配体的表达是破骨细胞形成所必需的，并且由转录因子c-fos、PU.1和NF-κ B调节的基因的活化也是必需的。NF-κ B调节破骨细胞生成细胞因子IL-6、IL-1和TNF的表达，其表达在炎性骨疾病中和响应于雌激素缺乏而上调。这些细胞因子也防止破骨细胞凋亡，绝经后骨吸收增加可能部分是由于骨表面破骨细胞寿命延长。NF-κ B也被证明可以阻止TNF-和FAS配体诱导的某些细胞类型的凋亡，因此可能参与破骨细胞寿命的调节。因此，NF-kappaB不仅可以调节正常骨重建中破骨细胞的形成，还可以调节绝经后破骨细胞的增加和寿命的延长。然而，NF-κ B介导破骨细胞中破骨细胞的这些活动的分子机制在很大程度上是未知的，可能涉及破骨细胞及其前体和成骨细胞中的多种信号通路。我们建议使用体外和体外方法的组合来研究NF-κ B在破骨细胞形成、活性和存活中的作用。我们的具体目标是确定NF-κ B在1）破骨细胞形成2）由细胞因子和雌激素缺乏诱导的破骨细胞生成的上调和3）破骨细胞凋亡的调节中的作用。破骨细胞前体沿着分化途径的进展以形成成熟的破骨细胞; 2）雌激素撤除后破骨细胞生成的上调;和3）通过防止破骨细胞经历凋亡而用于破骨细胞的存活。了解NF-kappaB在破骨细胞生成和生存中的作用可能会导致开发出专门用于抑制绝经后骨质疏松症等骨吸收增加的疾病的新治疗药物。

Osteoclasts are required for the normal development of bone during endochondral osification and for the resorption of worn-out bone in the adult skeleton during normal bone remodeling. They also mediate the increased bone loss that occurs in association with inflammation in bone and estrogen deficiency following menopause. Recent studies indicate that expression of M-CSF and RANK (receptor activation of NF-kappaB) ligand is required for osteoclast formation and that activation of genes regulated by the transcription factors, c-fos, PU.1 and NF-kappaB is also necessary. NF-kappaB regulates the expression of the osteoclastogenic cytokines, IL-6, IL-1, and TNF whose expression is up-regulated in inflammatory bone diseases and in response to estrogen deficiency. These cytokines also prevent osteoclast apoptosis, and the increased bone resorption seen after the menopause may in part be due to prolongation of osteoclast life spans on bone surfaces. NF-kappaB has also been shown to prevent TNF- and FAS ligand-induced apoptosis of some cell types and therefore may be involved in the regulation of osteoclast life span. Thus, NF-kappaB may regulate not only the formation of osteoclasts in normal bone remodeling, but also the increased production and prolonged life spans after the menopause. However, the molecular mechanisms whereby NF-kappaB mediates these activities in osteoclasts in osteoclasts are largely unknown and are likely to involve multiple signaling pathways in osteoclasts and their precursors and osteoblasts. We propose to use a combination of in vitro and in vitro approaches to study the role of NF- kappaB in osteoclast formation, activity and survival. Our specific aims are to determine the role of NF-kappaB in 1) osteoclast formation 2) the up- regulation of osteoclastogenesis induced by cytokines and estrogen deficiency and 3) the regulation of osteoclast apoptosis Our underlying hypothesis is that NF-kappaB is required for the activation of genes encoding cytokines which are essential for 1) the progression of osteoclast precursors along a differentiation pathway to form mature osteoclasts; 2) the up-regulation of osteoclastogenesis following estrogen withdrawal; and 3) for the survival of osteoclasts by preventing them from undergoing apoptosis. Understanding the role of NF-kappaB in osteoclastogenesis and survival could lead to the development of new therapeutic agents designed specifically to inhibit bone resorption in conditions, such as postmenopausal osteoporosis, in which it is increased.