Growth hormone regulating chondrocyte metabolism for osteoarthritis development

项目摘要 大多数老年人(约60岁)的关节有一些骨关节炎(OA)的迹象。不幸的是，在那里 由于我们缺乏对潜在的病理生理学的洞察，目前还没有针对骨性关节炎的疾病修正疗法。GH是 FDA批准的一种药物用于治疗某些疾病，如生长激素缺乏症(GHD)。此外，GH 随着时间的推移，分泌物减少，导致一些老年人考虑使用生长激素替代作为一种手段 对抗与衰老相关的疾病。然而，GH的过量生产或长期使用已被报告为 有许多副作用，包括关节退变和关节疼痛。确定生长激素的作用机制 在衰老过程中导致关节细胞功能障碍可以提供有效的干预和治疗策略， 减少骨质疏松症的发生率和影响。我们的初步研究表明，生长激素基因的过度表达 使小鼠发生进行性关节退行性变，同时通过全身性生长激素阻断生长激素的作用 受体的破坏保护小鼠免受骨性关节炎的侵袭。我们发现生长激素强烈地改变了细胞的代谢。 软骨中的细胞(即软骨细胞)。然而，目前尚不清楚是否阻断生长激素对软骨组织的作用 会起到保护作用。在我们的初步数据和文献的指导下，我们将通过三个方面来研究这个问题 具体目的：目的1.确定通过软骨特异性缺失GHR来阻断GH对软骨的作用 影响骨性关节炎的发育；目的2.确定生长激素促进软骨细胞肥大的机制 变化与办公自动化的发展。目的3.确定生长激素受体拮抗剂(GHA)是否能保护小鼠免受 发展办公自动化。已建立的小鼠生长激素过度表达和生长激素受体组织特异性缺失模型 将被用来研究增强或抑制软骨中生长激素作用对骨关节炎病理的影响。在……里面 体内和体外代谢谱方法将被用来确定操纵生长激素的效果 软骨细胞细胞代谢的信号转导。最后但同样重要的是，一种独特的鼠标模型被用于 Pegvisomant是FDA批准的治疗肢端肥大症的药物，该药的发现将用于测试是否可以阻断生长激素 有益于关节健康。这项研究的成功完成预计将提供更全面的 了解生长激素如何影响关节细胞功能，为提供新的治疗靶点提供潜在的 骨性关节炎治疗。

Project Summary Most older adults (~60 years of age) have some signs of osteoarthritis (OA) in their joints. Unfortunately, there are no disease-modifying therapies for OA due to our lack of insight into the underlying pathophysiology. GH is an FDA approved drug to treat certain diseases such as growth hormone deficiency (GHD). Additionally, GH secretion decreases over time, causing some older adults to consider the use of GH replacement as a means to counteract aging related conditions. However, over-production or prolonged usage of GH has been reported to have many side effects including joint degeneration and joint pain. Identifying the mechanisms by which GH causes joint cell dysfunction during aging could inform effective interventions and therapeutic strategies that reduce the incidence and impact of OA. Our preliminary studies have shown that over-expression of GH gene in mice predispose mice into progressive joint degeneration, while blocking GH action through systemic GH receptor disruption protect mice from developing OA. We showed that GH robustly altered the metabolism of cells (i.e, chondrocytes) in cartilage. Yet, it is still unknown if blocking GH’s action specifically on cartilage tissue would be protective. Guided by our preliminary data and the literature, we will investigate this question via three specific aims: Aim 1. Determine how blocking GH action on cartilage through cartilage specific deletion of GHR affects OA development; Aim 2. Determine the mechanisms by which GH promotes chondrocyte hypertrophic changes and OA development. Aim 3. Determine if GH receptor antagonism (GHa) protects mice from developing OA. Well-established mouse models GH over-expression and GH receptor tissue specific deletion will be used to examine the consequences of enhancing or inhibiting GH action in cartilage on OA pathology. In vivo and in vitro metabolic profiling methods will be leveraged to determine the effects of manipulating GH signaling on chondrocyte cellular metabolism. Last but not least, a unique mouse model that was used for discovery of Pegvisomant, an FDA approved drug for treating acromegaly, will be used to test if blocking GH is beneficial for joint health. Successful completion of this research is expected to provide more comprehensive understanding of how GH affects joint cell functions, offering the potential to provide new therapeutic targets for OA treatment.