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分子信号的复杂相互作用 (OCs)和骨形成成骨细胞（OB）。OB系细胞在OC形成中的整体作用，通过 NF-kB配体（RANKL）和骨保护素的受体激活剂的产生得到了充分描述。但对于 为了保持骨骼的完整性，骨形成必须与骨吸收相匹配--也就是说，骨水泥必须“反馈” 到OB。虽然破骨细胞：成骨细胞偶联的机制知之甚少，但很明显， 这种相互作用的结果在骨骼疾病。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另一端，骨形成继续 尽管OC功能失调，吸收水平非常低，导致OC丰富的骨硬化症（字面意思是“结石 骨”）。这种罕见的疾病家族的特点是异常致密，骨质疏松骨。在其常染色体 隐性形式，骨硬化症是潜在的致命性，由于骨髓和骨髓基质细胞浸润 失败R21的母提案寻求获得关键的实验支持的假设，研究 骨硬化症中OC：OB偶联功能障碍将揭示驱动骨过剩的新分子机制 OC-错误定向的OB形成并取代骨髓龛。拟议的补充项目 扩展了骨硬化模型的分析，将最近发现的 骨硬化症由于SLC 4A 2突变。

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.