Growth hormone regulating chondrocyte metabolism for osteoarthritis development

生长激素调节软骨细胞代谢促进骨关节炎的发展

• 批准号: 10730575
• 负责人: Shouan Zhu
• 金额: $ 50.2万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730575
• 关键词: Acromegaly; Adult; Affect; Age; Age Years; Aging; Arthralgia; Biological Assay; Biological Markers; Blood; Bone Spur; Cartilage; Cartilage Matrix; Cell physiology; Cells; Cellular Metabolic Process; Childhood; Chondrocytes; Clinical; Collagen; Contralateral; Data; Degenerative polyarthritis; Development; Diabetes Mellitus; Disease; Elderly; Enzymes; Epiphysial cartilage; Epitopes; FDA approved; Functional disorder; Genes; Genus Hippocampus; Growth; Growth Hormone Receptor; Growth Hormone Secreting Pituitary Adenoma; Health; Hip region structure; Histologic; Hormonal; Hormone secretion; Human; Hyperalgesia; Hypertrophy; In Vitro; Incidence; Inflammation; Interleukin-1 beta; JAK2 gene; Joints; Knee; Knee joint; Knowledge; Laboratories; Lesion; Lipolysis; Literature; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolism; Methods; Mission; Mus; Neck; Pain; Paraffin; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Process; Production; Public Health; Regulation; Reporting; Research; Role; Serum; Signal Transduction; Skeletal system; Somatotrophin increased; Somatotropin; Spirometry; Stat5 protein; Synovitis; TNF gene; Testing; Therapeutic; Time; Tissues; United States National Institutes of Health; aggrecan; antagonist; anti aging; articular cartilage; bovine growth hormone; cartilage degradation; collagenase 3; cost; disability; effective intervention; fatty acid oxidation; femur head; growth hormone deficiency; hormonal signals; in vivo; insight; joint destruction; joint function; liquid chromatography mass spectrometry; metabolomics; mouse model; new therapeutic target; novel; off-label use; overexpression; pegvisomant; postnatal; pressure; prevent; public health relevance; receptor; side effect

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.

项目摘要 大多数老年人（约60岁）的关节中有一些骨关节炎（OA）的迹象。不幸的是，那里 由于我们对潜在的病理生理学缺乏洞察力，因此没有针对OA的疾病调整疗法。 GH是 FDA批准药物治疗某些疾病，例如生长马缺乏症（GHD）。另外，GH 随着时间的流逝，分泌减少，导致一些老年人考虑使用GH替代品作为一种手段 抵消与衰老相关的条件。但是，据报道GH的生产过多或长期使用 具有许多副作用，包括关节变性和关节疼痛。识别GH的机制 导致衰老期间的联合细胞功能障碍可以为有效的干预措施和治疗策略提供信息 减少OA的事件和影响。我们的初步研究表明，GH基因的过表达 在小鼠中，小鼠倾向于进行渐进的关节变性，同时通过全身性GH阻塞GH作用 受体破坏可以保护小鼠免受OA的发展。我们证明GH强烈改变了 软骨中的细胞（即软骨细胞）。然而，仍然未知是否专门阻止GH的动作在软骨组织上 将受到保护。在我们的初步数据和文献的指导下，我们将通过三个 特定目的：目标1。确定如何通过软骨特异性缺失对软骨的阻塞作用 影响OA的发展；目标2。确定GH促进软骨细胞肥厚的机制 变化和OA的发展。目标3。确定GH受体拮抗作用（GHA）是否保护小鼠免受 开发OA。公认的小鼠模型GH过表达和GH受体组织特异性缺失 将用于检查软骨对OA病理学的增强或抑制GH作用的后果。在 体内和体外代谢分析方法将被利用以确定操纵GH的影响 在软骨细胞代谢上的信号传导。最后但并非最不重要的一点是，用于用于的独特鼠标模型 FDA批准的治疗肢端肥大的药物Pegvisomant的发现将用于测试阻塞GH是否为 对联合健康有益。预计这项研究的成功完成将提供更全面的 了解GH如何影响关节细胞功能，从而为提供新的治疗靶标的潜力 OA处理。