Diversity Supplement: Talking Back: Leveraging dysfunctional osteoclasts to identify novel pathways of osteoclast-osteoblast communication

项目摘要 适当的骨结构依赖于骨吸收破骨细胞之间复杂的分子信号相互作用 (OCS)和成骨细胞(OBS)。OB系细胞在OC形成中的不可或缺的作用 核因子-kB受体激活剂配体(RANKL)和骨整合蛋白的生产被描述得很好。然而，对于 要保持骨骼的完整性，骨形成必须与吸收相匹配--也就是说，OC必须“顶嘴”。 转到妇产科。虽然破骨细胞的机制：成骨细胞偶联知之甚少，但很明显，失调 这种相互作用会导致骨骼疾病。在光谱的一端，吸收超过形成，导致 常见且昂贵的骨质疏松症和骨折。在光谱的另一端，骨形成继续 尽管OC功能障碍，但吸收水平非常低，导致OC丰富的骨化病(字面意思为“结石” 骨“)。这种罕见的疾病家族以异常致密的骨硬化性骨为特征。在其常染色体中 隐性骨化症是一种潜在的致命疾病，其原因是骨髓和骨髓中的基质细胞渗入。 失败了。父R21提案寻求获得关键的实验支持，以支持研究 骨化病中功能失调的OC：OB偶联将揭示驱动过剩骨量的新分子机制 用OC错误定向的OB形成和替换骨髓龛。拟议的补充项目 扩展了对骨化症模型的分析，纳入了最近发现的 SLC4A2基因突变引起的骨化病。

Project Summary Proper bone structure relies on a complex interplay of molecular signals between bone resorbing osteoclasts (OCs) and bone forming osteoblasts (OBs). The integral role of OB lineage cells in OC formation, through production of receptor activator of NF-kB ligand (RANKL) and osteoprotegrin, is well described. However, for skeletal integrity to be maintained, bone formation must be matched to resorption - that is, OC must “talk back” to OB. While the mechanism of osteoclast:osteoblast coupling is poorly understood, it is clear that dysregulation of this interaction results in bone disease. At one end of the spectrum, resorption exceeds formation resulting in the common and costly osteoporosis and fractures. At the other end of the spectrum, bone formation continues despite dysfunctional OC with very low levels of resorption, resulting in OC-rich osteopetrosis (literally, “stone bone”). This rare family of diseases is characterized by abnormally dense, osteosclerotic bone. In its autosomal recessive form, osteopetrosis is potentially fatal due to stromal cell infiltration of the bone marrow and marrow failure. The parent R21 proposal seeks to obtain critical experimental support for the hypothesis that studying dysfunctional OC:OB coupling in osteopetrosis will reveal novel molecular mechanisms driving excess bone formation and replacement of the marrow niche with OC-misdirected OB. The proposed supplement project extends the analysis of osteopetrosis models to incorporate a mouse model of the very recently identified osteopetrosis due to mutations in SLC4A2.