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）的关节都有骨关节炎（OA）的迹象。可惜 由于我们缺乏对基础病理生理学的了解，因此没有针对OA的疾病改善疗法。GH是 一种FDA批准的治疗某些疾病如生长激素缺乏症（GHD）的药物。此外，GH 随着时间的推移，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， 对抗衰老相关的疾病。然而，据报道，过度生产或长期使用GH， 有许多副作用，包括关节退化和关节疼痛。确定GH的机制 在衰老过程中引起关节细胞功能障碍可以为有效的干预和治疗策略提供信息， 降低OA的发病率和影响。我们的初步研究表明，GH基因的过表达 在小鼠中，使小鼠易患进行性关节变性，同时通过全身GH阻断GH作用， 受体破坏保护小鼠免于发展OA。我们发现，生长激素强烈改变了代谢， 细胞（即软骨细胞）。然而，它仍然是未知的，如果阻止生长激素的作用，特别是对软骨组织 会有保护作用根据我们的初步数据和文献，我们将通过三个方面来研究这个问题。 具体目标：目标1。确定如何通过GHR的软骨特异性缺失来阻断GH对软骨的作用 影响OA发展;目标2.确定GH促进软骨细胞肥大的机制 变化与发展。目标3.确定GH受体拮抗剂（GHa）是否保护小鼠免受 发展OA。成熟的GH过表达和GH受体组织特异性缺失小鼠模型 将用于检查增强或抑制软骨中GH作用对OA病理学的影响。在 将利用体内和体外代谢分析方法来确定操纵GH的影响， 软骨细胞代谢的信号传导。最后但并非最不重要的是，一种独特的小鼠模型， Pegvisomant是一种FDA批准的治疗肢端肥大症的药物，它的发现将被用来测试阻断GH是否是一种有效的治疗方法。 有益于关节健康。本研究的成功完成，有望为我国的经济发展提供更全面的 了解生长激素如何影响关节细胞功能，提供了提供新的治疗靶点的潜力， OA治疗。