Osteocyte Control of Bone Remodeling

摘要 破骨细胞的形成依赖于核因子B配体的细胞因子受体激活剂，其作用是 被诱骗受体护骨素(OPG)抑制。骨细胞是RANKL和WE的重要来源 最近发现，成骨细胞，而不是骨细胞，是抑制OPG的重要来源 松质骨吸收。相比之下，成骨细胞和骨细胞只提供一部分OPG 保护皮质骨。因此，提供保护大脑皮层大区域的OPG的细胞的身份 骨骼尚不清楚，但可能涉及成骨前体细胞和血管内皮细胞，这两者都是 快递OPG。先前的研究表明，β-连环蛋白的一个主要功能是促进OPG的表达。 骨细胞。我们发现成骨细胞而不是骨细胞是OPG的主要来源，这就需要一种 重新评估β-连环蛋白在骨细胞中的作用。先前关于β-连环蛋白功能丧失的研究 由于缺乏能够区分成骨细胞和骨细胞的Cre驱动菌株，以及 晚期成骨细胞中β-连环蛋白缺失引起的骨丢失。成骨细胞是一种 OPG的重要来源还表明，骨吸收和反弹后骨丢失的快速增加 停止抗RANKL(Denosumab)治疗可能部分是由于缺乏成骨细胞，以及 因此，OPG在停产后的一段时间内。基于这些发现，我们提出了假设 成骨祖细胞或血管内皮细胞是OPG保护皮质的重要来源 骨细胞中的β-连环蛋白途径有助于骨重建，而不受其控制。 OPG的表达。我们还提出，成骨细胞的缺乏，从而导致OPG的反弹。 停用地诺单抗后的吸收。目标1将确定控制大脑皮层的OPG的细胞来源 在使用PRX1-CRE小鼠的间充质祖细胞中通过删除条件OPG等位基因进行骨吸收，以及 使用Tek-CRE小鼠的血管内皮细胞，并将其对皮质骨和OPG的影响进行比较。 零老鼠。目的2通过使用SOST-CRE删除β-连环蛋白来确定β-连环蛋白在骨细胞中的作用 小鼠，它删除了骨细胞中的目标基因，但不是成骨细胞。目标3将决定反弹是否 停用地诺单抗引起的吸收，部分原因是成骨细胞的严重缺乏 用地诺单抗处理的新型人源化RANKL小鼠系生产OPG。这些老鼠将被用来 绘制与停用地诺单抗相关的细胞和分子状态图，并确定 应用抗硬化素抗体促进成骨细胞形成能否恢复OPG水平 改善反弹吸收。

Abstract Osteoclast formation depends on the cytokine receptor activator of NFB ligand (RANKL), whose actions are inhibited by the decoy receptor osteoprotegerin (OPG). Osteocytes are an important source of RANKL and we have recently shown that osteoblasts, but not osteocytes, are an essential source of the OPG that suppresses resorption of cancellous bone. In contrast, osteoblasts and osteocytes provide only a portion of the OPG protecting cortical bone. Thus, the identity of the cells providing the OPG that protects large regions of cortical bone remains unclear, but may involve osteoblast progenitors and vascular endothelial cells, both of which express OPG. Previous studies suggest that a major function of beta-catenin is to promote OPG expression in osteocytes. Our finding that osteoblasts, but not osteocytes, are a major source of OPG necessitates a reevaluation of the role of beta-catenin in osteocytes. Previous beta-catenin loss-of-function studies have been hampered by the lack of Cre driver strains that can distinguish between osteoblasts and osteocytes and by the dramatic bone loss caused by beta-catenin deletion in late-stage osteoblastic cells. That osteoblasts are an important source of OPG also suggests that the rapid increase in resorption and rebound bone loss following discontinuation of anti-RANKL (denosumab) therapy may be due, in part, to the absence of osteoblasts, and thus OPG, during the period following discontinuation. Based on these findings, we propose the hypotheses that osteoblast progenitors or vascular endothelial cells are important sources of the OPG protecting cortical bone and that the beta-catenin pathway in osteocytes contributes to bone remodeling independent of its control of OPG expression. We also propose that the lack of osteoblasts, and thus OPG, contributes to the rebound resorption following discontinuation of denosumab. Aim 1 will identify cellular sources of OPG that control cortical bone resorption by deleting a conditional OPG allele in mesenchymal progenitors using Prx1-Cre mice, and vascular endothelial cells using Tek-Cre mice, and compare the effects on cortical bone to those seen in OPG- null mice. Aim 2 will determine the role of beta-catenin in osteocytes by deletion of beta-catenin using Sost-Cre mice, which delete target genes in osteocytes but not osteoblasts. Aim 3 will determine whether the rebound resorption caused by discontinuation of denosumab results in part from the profound lack of osteoblasts producing OPG using a novel humanized RANKL mouse line treated with denosumab. These mice will be used to map the cellular and molecular conditions associated with discontinuation of denosumab and to determine whether promotion of osteoblast formation via anti-sclerostin antibody administration can restore OPG levels and ameliorate rebound resorption.