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

项目概要 正确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 (OC) 和成骨成骨细胞 (OB)。 OB谱系细胞在OC形成中的不可或缺的作用，通过 NF-kB 配体 (RANKL) 和骨保护素受体激活剂的生产已有详细描述。然而，对于 要维持骨骼完整性，骨形成必须与骨吸收相匹配——也就是说，OC 必须“顶嘴” 到产科。虽然破骨细胞：成骨细胞偶联的机制尚不清楚，但很明显，失调 这种相互作用会导致骨病。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。另一方面，骨形成仍在继续 尽管功能失调的 OC 具有非常低的吸收水平，导致富含 OC 的骨硬化症（字面意思是“石头”） 骨”）。这种罕见疾病的特点是骨质异常致密、骨质硬化。在其常染色体中 隐性形式，石骨症由于骨髓和骨髓的基质细胞浸润而可能致命 失败。父 R21 提案旨在为以下假设获得关键的实验支持：研究 骨石化症中功能失调的 OC:OB 耦合将揭示驱动多余骨的新分子机制 骨髓生态位的形成和用 OC 误导的 OB 替代。拟议的补充项目 扩展了石骨症模型的分析，纳入了最近发现的小鼠模型 SLC4A2 突变导致石骨症。

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.