Development of Pharmacological Treatment of Osteochondromas

骨软骨瘤药物治疗研究进展

• 批准号: 10571866
• 负责人: MOTOMI ENOMOTO-IWAMOTO
• 金额: $ 30.59万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571866
• 关键词: Ablation; Adolescence; Agonist; Benign; Biochemical; Biological; Biological Assay; Biology; Bone Surface; Cartilage; Cartilaginous exostosis; Cells; Childhood; Chondrocytes; Chondrogenesis; Chondrogenic Neoplasm; Chondrosarcoma; Clinical Management; Deformity; Development; Differentiation and Growth; Disease Management; Disease model; Distal; Down-Regulation; EXT1 gene; EXT2 gene; Elements; Energy Metabolism; Epiphysial cartilage; Excision; Fibroblast Growth Factor; Gene Expression Profiling; Genetic Transcription; Glycolysis; Goals; Growth; Health; Heparitin Sulfate; Hereditary Multiple Exostoses; Histologic; Histopathology; Human; Hypertrophy; In Vitro; Lead; Link; Longitudinal Studies; Malignant - descriptor; Modeling; Molecular; Mus; Mutation; Nature; Nerve Pain; Nerve compression syndrome; Nuclear; Operative Surgical Procedures; Pain; Pathogenesis; Pharmacological Treatment; Pharmacotherapy; Phase III Clinical Trials; Physical Function; Population; Procedures; Proliferating; Radiation therapy; Regulation; Research; Resistance; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Time; Treatment Efficacy; Tumor stage; Up-Regulation; Width; beta catenin; bone; cartilaginous; chemotherapy; combat; drug candidate; high risk; in vivo; innovation; insight; mouse model; neoplastic; neoplastic cell; novel; novel therapeutics; osteoprogenitor cell; pharmacologic; progenitor; response; retinoic acid receptor gamma; skeletal; smoothened signaling pathway; standard of care; stem; transcriptome; transcriptome sequencing; tumor; tumor growth

Abstract Osteochondromas are the most common skeletal tumors during childhood or adolescence. The tumors grow over time and cause skeletal deformities, nerve compression, pain and other health problems. Osteochondromas are primarily treated surgically and thereby treatment for multiple osteochondromas may require repetitive surgery. Osteochondromas located at a high-risk site for surgery may be managed non- surgically, however, this increases the potential for progression to malignant chondrosarcomas. The final goal of this project is to develop non-surgical therapies that would stop osteochondroma formation and growth in an effective manner. Multiple osteochondromas can be caused by mutations in the heparan sulfate synthases EXT1 or EXT2. Research from our lab and other groups have indicated that reduction in heparan sulfate induce alterations of multiple signaling pathways, leading to osteochondromas. Our long-term studies on nuclear retinoic acid receptor gamma (RARγ) reveal that (1) pharmacologic activation of RARγ strongly inhibits ectopic cartilage formation; (2) RARγ is expressed in cartilage elements in mouse and human osteochondromas; and (3) RARγ agonists inhibited ectopic cartilage formation and induced involution of existing cartilaginous tumor masses in the osteochondroma mouse model. We hypothesize that RARγ could be a novel pharmaco-therapeutic target for osteochondromas by an anti-chondrogenic action and pro- hypertrophic action. The cell origin of osteochondromas remains to be clarified. We have recently discovered a novel cell population of chondroprogenitors contributing to appositional width growth of growth plate. These cells are Wnt-responsive skeletal progenitors and reside in growth plate and the neighboring perichondrium. We hypothesize that aberrant regulation of these progenitors induce osteochondromas and RARγ signaling ameliorates their altered nature. To test these hypotheses, we propose three aims: Aim 1, To establish therapeutic efficacy of RARγ agonists and examine their molecular actions in the mouse osteochondroma model; Aim 2, To determine the cells that contribute to osteochondroma formation and growth and their response to RARγ signaling; and Aim3, To investigate the actions of RARγ agonists on human osteochondroma cells. The study involves diverse experimental procedures encompassing drug treatment with mice, histological and molecular biological assessments of the mouse disease models, high throughput gene expression analysis and study on human tumor cells. The Project will test innovative ideas on the pathogenesis of osteochondroma and equally innovative ideas on how to combat them therapeutically.

摘要 骨软骨瘤是儿童或青少年时期最常见的骨骼肿瘤。肿瘤 随着时间的推移而生长，并导致骨骼畸形、神经压迫、疼痛和其他健康问题。 骨软骨瘤主要通过外科手术治疗，因此治疗多发性骨软骨瘤可以 需要反复的手术骨软骨瘤位于手术的高风险部位，可采用非手术治疗。 然而，外科手术增加了发展为恶性软骨肉瘤的可能性。最终目标 该项目的目的是开发非手术疗法，可以阻止骨软骨瘤的形成和生长， 有效的方式。多发性骨软骨瘤可由硫酸乙酰肝素酶突变引起 EXT 1或EXT 2我们实验室和其他小组的研究表明，硫酸乙酰肝素的减少 诱导多种信号通路的改变，导致骨软骨瘤。我们长期的研究， 核视黄酸受体γ（RARγ）显示：（1）RARγ的药理学激活强烈抑制 （2）RARγ在小鼠和人的软骨细胞中表达 （3）RARγ激动剂抑制异位软骨形成并诱导软骨退化。 骨软骨瘤小鼠模型中存在的软骨肿瘤块。我们假设RARγ可以 通过抗软骨形成作用成为骨软骨瘤新的药物治疗靶点， 肥大作用骨软骨瘤的细胞来源仍有待澄清。我们最近发现了一个 软骨祖细胞的新细胞群有助于生长板的并置宽度生长。这些 细胞是Wnt-反应性骨骼祖细胞，并驻留在生长板和邻近的软骨膜中。 我们假设这些祖细胞的异常调节诱导骨软骨瘤和RARγ信号转导 改变了他们的性格。为了验证这些假设，我们提出了三个目标：目标1，建立 RARγ激动剂的治疗效果，并检查它们在小鼠骨软骨瘤中的分子作用 目的2，确定有助于骨软骨瘤形成和生长的细胞及其表达。 目的：研究RARγ激动剂对人RARγ信号转导的作用。 骨软骨瘤细胞该研究涉及不同的实验程序，包括药物治疗， 小鼠，小鼠疾病模型的组织学和分子生物学评估，高通量基因 人肿瘤细胞的表达分析和研究。该项目将测试创新的想法， 骨软骨瘤的发病机制和同样创新的想法，如何打击他们的治疗。

项目成果

Selective Agonists of Nuclear Retinoic Acid Receptor Gamma Inhibit Growth of HCS-2/8 Chondrosarcoma Cells

核视黄酸受体γ的选择性激动剂抑制HCS-2/8软骨肉瘤细胞的生长

• DOI: 10.1002/jor.24555
• 发表时间: 2019
• 期刊: J Orthop Res
• 影响因子: 2.8
• 作者: W. P. Shield;3rd;A. Cellini;H. Tian;K. Wilson;Y. Dan;J. M. Abzug;S. Garcia;N. Moritani;I. Alferiev;M. Chorny;M. Takigawa;V. Y. Ng;M. Iwamoto.M. Enomoto-Iwamoto.
• 通讯作者: M. Iwamoto.M. Enomoto-Iwamoto.