Parathyroid Hormone-related Peptide

描述(申请人提供)：我们已经创造了一个等位基因PTHrP-LacZ敲门小鼠，它提供了一个简单而敏感的PTHrP基因表达报告。PTHrP-LacZ小鼠在许多不同的位置显示了PTHrP基因的表达，包括几个以前没有被认识或被低估的地方。这些包括：1)肌腱和韧带插入皮质骨的位置(统称为内陷)，2)骨膜本身，特别是在骨生长过程中的骨膜，以及3)关节软骨的表层。在所有这些部位，PTHrP基因似乎都是机械诱导的。我们还没有发现PTHrP/LacZ在任何内部骨细胞群中的表达。 我们认为，PTHrP在软骨内骨的“门”起作用，即在骨骼元素之间以及与周围肌肉和结缔组织的界面上发挥作用。目的1.我们将研究PTHrP、PPR和细胞标志物在选定的骨膜部位和末端的表达，以便：a)确定参与这些部位旁分泌信号的细胞，b)使AIMS 2和3中提出的功能实验成为可能。我们还培育了一个含有LacZ等位基因的PTHrP缺失小鼠，作为印度刺猬调节PTHrP基因表达的报告系统。目标2包括两个重叠的次级目标。其一涉及甲状旁腺激素相关蛋白表达和软骨细胞或骨细胞功能的机械调节(S)，包括骨膜、纤维软骨和纤维肌腱。第二种是考虑甲状旁腺素受体在骨膜中的特定功能，包括a)力驱动的骨膜骨形成的介导性，b)线性生长过程中干干端和干骨干端模型化的调节，c)甲状旁腺素受体可能参与骨膜的性别二型性。目的3.我们将利用硬化轴和/或Periostin基因来建立PTHrP在骨膜和肌腱膜中有条件地缺失的小鼠模型。与公共卫生相关。大多数骨骼都是从最初的软骨霉菌发展而来的。这种骨骼由两个独立的部分组成：内部(或骨内)骨和外部(或骨膜)骨。骨内膜的进化主要是为了满足生殖需求，并且主要受雌激素的调节。骨膜是男性更大更强壮的骨骼，主要受雄激素和机械力的调节(并受雌激素的抑制)。我们已经发现甲状旁腺激素相关蛋白(PTHrP)存在于骨膜、韧带和肌腱的骨膜内，也存在于关节软骨中。在所有这些部位，PTHrP的产生都受到机械力的调节。我们认为PTHrP调节长骨上的软骨和骨细胞功能，即在长骨之间以及与周围肌肉和结缔组织的交界处。这些功能的例子包括甲状旁腺素调节机械力对骨骼的塑造，骨骼生长时的造型，以及性类固醇对骨骼大小的调节。

DESCRIPTION (provided by applicant): We have created an allelic PTHrP-lacZ knockin mouse that provides a simple and sensitive reporter of PTHrP gene expression. The PTHrP-lacZ mouse demonstrates PTHrP gene expression in a wide variety of locations, including several that were previously unappreciated or underappreciated. These include: 1) the insertion sites of tendons and ligaments into cortical bone (collectively referred to as entheses), 2) the periosteum itself, particularly during bone growth, and 3) superficial layers of articular cartilage. In all of these sites, the PTHrP gene seems to be mechanically-induced. We have not identified PTHrP/lacZ expression in any internal bone cell population. We propose that PTHrP functions "at the gates" of endochondral bones, namely, at the interface of skeletal elements with each other and with surrounding muscles and connective tissues. Aim 1. We will characterize PTHrP, PPR, and cell marker expression in selected periosteal sites and entheses in order to: a) identify the cells that participate in paracrine signaling in these sites and b) enable the functional experiments proposed in Aims 2 and 3. We have also bred a single lacZ allele-containing PTHrP-null mouse that serves as a reporter system for Indian hedgehog regulation of PTHrP gene expression. Aim 2 comprises two overlapping subaims. One involves mechanical regulation of PTHrP expression and chondrocyte or bone cell function(s) in the periosteum, fibrocartilage, and fibrous entheses. The second considers specific candidate PTHrP functions in the periosteum, including a) mediation of force-driven periosteal bone formation, b) regulation of the modeling of the metaphysis and diaphysis during linear growth, and c) potential PTHrP involvement in the sexual dimorphism of periosteal bone. Aim 3. We will employ the scleraxis and/or periostin genes in order to create mouse models in which PTHrP is conditionally deleted in the periosteum and entheses. PUBLIC HEALTH RELEVANCE. Most bones develop from an initial cartilagenous mold. Such bones are comprised of two separate compartments: internal (or endosteal) bone and external (or periosteal) bone. Endosteal bone evolved principally to subserve reproductive demands and is primarily regulated by estrogen. Periosteal bone accounts for the larger and stronger skeleton in the male and is regulated primarily by androgens and mechanical forces (and inhibited by estrogen). We have identified parathyroid hormone-related protein (PTHrP) in the periosteum and ligament and tendon insertions into periosteal bone and also in articular cartilage the joints. In all of these sites, PTHrP production is regulated by mechanical force. We propose that PTHrP regulates cartilage and bone cell functions "at the gates" on long bones, namely, at the interface of the bones with each other and with surrounding muscles and connective tissues. Examples of such functions include PTHrP mediation of the shaping of bones by mechanical force, the sculpting of bones as they grow, and the sex steroid modulation of skeletal size.