The Role of Podocalyxin in Osteoclast Activity and Bone Metabolism

描述(申请人提供)：目前治疗骨质疏松症的方法，如双磷酸盐，靶向破骨细胞介导的骨吸收。虽然这些药物有效地减少了骨丢失，但伴随着骨重建的减少，导致骨形成和修复的减少，这一点变得复杂起来。越来越多的证据表明，破骨细胞的存在是成骨细胞骨形成所必需的。因此，该项目的长期目标是确定潜在的治疗靶点，以抑制破骨细胞的活性，同时保留破骨细胞对成骨细胞和骨形成的合成代谢作用。在不降低破骨细胞的合成代谢作用的情况下抑制破骨细胞活性的一个潜在靶点是Podocalysin(PODXL)。PODXL此前被认为是一种由造血系细胞表达的细胞黏附的介体。初步数据表明，在造血系/破骨细胞前体(Vav/PODXLdel)中特异性缺失PODXL会导致雌性成年小鼠高骨量表型和成骨细胞数量增加。虽然这些小鼠表现出破骨细胞数量的增加，但这些破骨细胞的吸收作用受到了损害。特别有趣的是，这种高骨量表型仅在雌性小鼠中明显，这表明PODXL的丢失因特定的性类固醇的存在或缺乏而加剧。Vav/PODXLdel骨髓源性破骨细胞的rac1 GTP酶活性降低。几个小组已经证明，雌激素降低了rac1的激活，这有助于动物模型中的性别特异性表型。我的项目的中心假设是PODXL是最佳rac1激活所必需的；PODXL的缺失会加剧雌激素抑制rac1激活的效果，导致破骨细胞再吸收功能受损，并导致雌激素充足的雌性小鼠的骨量增加。我的目标是在活体小鼠模型中表征性激素如何影响Vav/PODXLdel小鼠的骨表型，并确定PODXL调节rac1激活和破骨细胞性骨吸收的机制。了解PODXL促进破骨前细胞中rac1激活的机制以及循环性类固醇是如何影响这一作用的，可能会导致在不干扰破骨细胞对骨骼的合成代谢作用的情况下抑制破骨细胞活性的新的治疗靶点。 此外，研究性类固醇在Vav/PODXLdel骨表型中的作用可能有助于阐明绝经后和年龄相关骨丢失的机制。

DESCRIPTION (provided by applicant): Current treatments for osteoporosis, such as the bisphosphonates, target osteoclast-mediated bone resorption. While these agents effectively reduce bone loss, this is complicated by an associated decrease in bone remodeling resulting in diminished bone formation and repair. Mounting evidence suggests that the presence of osteoclasts is required for bone formation by osteoblasts. Thus, the long term goal of this project is to identify potential therapeutic targets to inhibit osteoclast activity while preservin the anabolic effects of osteoclasts on osteoblasts and bone formation. One potential target to inhibit osteoclast activity without reducing the anabolic effects of osteoclasts is podocalyxin (PODXL). PODXL has previously been identified as a mediator of cell adhesion expressed by cells of the hematopoietic lineage. Preliminary data show that deletion of PODXL specifically in the hematopoietic lineage/osteoclast precursors (Vav/PODXLdel) leads to a high bone mass phenotype in female adult mice and increased osteoblast numbers. While these mice exhibit increased osteoclast numbers, resorption by these osteoclasts is impaired. Of particular interest, this high bone mass phenotype is evident only in female mice suggesting that the loss of PODXL is exacerbated by the presence or absence of specific sex steroids. Vav/PODXLdel bone marrow derived osteoclasts exhibit reduced activation of the Rac1 GTPase. Several groups have demonstrated that Rac1 activation is reduced by estrogen and this contributes to sex specific phenotypes in animal models. The central hypothesis of my project is that PODXL is necessary for optimal Rac1 activation; deletion of PODXL exacerbates the effect of estrogen to inhibit Rac1 activation, leading to impaired osteoclast resorption and a high bone mass in estrogen-sufficient female mice. My objectives are to characterize how the bone phenotype of Vav/PODXLdel mice is impacted by sex steroids in an in vivo mouse model and to define the mechanism by which PODXL modulates Rac1 activation and osteoclastic bone resorption. Understanding the mechanism by which PODXL facilitates Rac1 activation in pre-osteoclasts and how this is impacted by circulating sex steroids may lead to novel therapeutic targets to inhibit osteoclast activity without disturbing the anabolic effects of osteoclasts on the skeleton. Additionally, studying the role of sex steroids in the Vav/PODXLdel bone phenotype may elucidate mechanisms that contribute to postmenopausal and age-related bone loss.