Central role for osteocytes in integration of endocrine signals during growth

描述（由申请人提供）：目前骨质疏松症和年龄相关性骨病的临床管理仅限于对症治疗，主要是通过使用抑制骨吸收的药物来减缓骨丢失速率。然而，骨质疏松症患者的数量呈指数级增长，与骨质疏松症管理相关的医疗保健费用也相应增加。因此，将我们的骨骼健康范式从治疗转变为预防以对抗骨质疏松症及其相关并发症的增加的能力将构成骨质疏松症临床管理方式的重大改进。预防骨质疏松症的一种方法是优化青春期生长期间的峰值骨获取。生长激素（GH）及其下游效应因子胰岛素样生长因子-1（IGF-1）在生长过程中通过不仅调节线性生长而且调节横向骨生长（决定骨强度的重要因素）在骨积累中起关键作用。长期目标是确定GH/IGF-1轴在正常生理和年龄相关性骨病中调节骨骼完整性的内分泌和自分泌/旁分泌机制。本申请的目的是阐明骨细胞中GH受体（GHR）的激活控制青春期生长期间骨积累的机制。最重要的假设是，骨细胞对GH的反应在调节骨量获得中起着核心作用，并且通过独立于GH对线性生长的影响的机制来实现。在强有力的初步数据的指导下，这一假设将通过追求以下三个具体目标进行检验：1。确定骨细胞特异性GHR调节骨生成的机制。2.确定骨细胞特异性GHR与PTH和sclerostin相互作用以调节峰值骨量的机制。3.确定骨细胞特异性GHR调节机械负荷合成代谢反应的机制。将使用已生成的骨细胞特异性GH受体敲除（GHRKO）小鼠实现所有目标。重要的是，该模型的初步表征显示了骨小梁增长变钝和皮质骨体积减少-尽管总体体型和骨长度正常。我们的新数据显示，骨骼中GH不敏感性损害PTH合成代谢作用，可能涉及骨中sclerostin的表达，将我们的结果与目前治疗干预的主要靶点的两种骨骼调节剂密切相关。所提出的方法是创新的，因为它第一次关注骨细胞不仅作为机械传感器和矿物质稳态的调节剂，而且作为生长过程中控制骨形成的内分泌信号的整合剂。此外，我们首次提供了一种直接的方法来确定在何种程度上局部GHR的行动是必要的骨细胞机械反应。这项研究意义重大，因为它有望促进我们对峰值骨量如何实现的理解，最终导致预防年龄相关性骨质流失的干预措施的发展。

DESCRIPTION (provided by applicant): Currently the clinical management of osteoporosis and age-related bone disease is limited to symptomatic treatment and is directed mainly at slowing the rate of bone loss by using agents that inhibit bone resorption. Yet, the number of patients with osteoporosis is growing exponentially and health care costs related to osteoporosis management are increasing accordingly. Thus, an ability to shift our paradigm of bone health from treatment to prevention to combat this rise in osteoporosis and its related complications would constitute a significant improvement in how osteoporosis is managed clinically. One such approach to preventing osteoporosis that holds promise is optimization of peak bone acquisition during pubertal growth. Growth hormone (GH) and its downstream effector insulin-like growth factor-1 (IGF-1) play critical roles in bone accrual during growth by regulating not only linear growth but also transversal bone growth, an important factor determining bone strength. The long-term goal is to determine the endocrine and autocrine/paracrine mechanisms by which the GH/IGF-1axis regulates skeletal integrity in normal physiology and age-related bone disease. The objective for this application is to elucidate the mechanisms by which activation of the GH receptor (GHR) in osteocytes controls bone accrual during pubertal growth. The overarching hypothesis is that osteocyte response to GH plays a central role in regulating the acquisition of bone mass, and does so via mechanisms independent from GH effects on linear growth. Guided by strong preliminary data, this hypothesis will be tested by pursuing the following three specific aims: 1. Determine the mechanisms by which osteocyte-specific GHR regulates osteogenesis. 2. Determine the mechanisms by which osteocyte-specific GHR interacts with PTH and sclerostin to regulate peak bone mass. 3. Determine the mechanism(s) by which osteocyte- specific GHR modulates anabolic response to mechanical loading. An already-generated osteocyte- specific GH-receptor knockout (GHRKO) mouse will be used to achieve all aims. Importantly, initial characterization of this model has revealed blunted trabecular bone accrual and decreased cortical bone volume - all despite normal overall body size and bone lengths. Our new data showing that GH insensitivity in bone impairs PTH anabolic effects possibly involving sclerostin expression in bone, links our results closely to two skeletal regulators that are currently major targets of therapeutic interventions. The proposed approach is innovative because it focuses for the first time on osteocytes not only as mechanosensors and regulators of mineral homeostasis, but also as integrators of endocrine signals that control bone formation during growth. Further, we offer for the first time a direct approach to determine the extent to which local GHR action is necessary for osteocyte mechanoresponse. The proposed research is significant because it is expected to advance our understanding of how peak bone mass is achieved, ultimately leading to the development of interventions for the prevention of age-related bone loss.