The Role of Extracellular Matrix Dysregulation in Heterotopic Ossification

细胞外基质失调在异位骨化中的作用

• 批准号: 10650140
• 负责人: Sun H Peck
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650140
• 关键词: Affect; Afghanistan; Aftercare; Amputation; Animal Model; Anti-Inflammatory Agents; Area; Atomic Force Microscopy; Automobile Driving; Biological Markers; Biological Process; Blast Injuries; Blood; Bone Growth; Brain; Burn injury; Chemicals; Chondroitinases; Collagen; Data; Deposition; Development; Direct Lytic Factors; Environment; Excision; Extracellular Matrix; Fibrosis; Gene Expression; Genetic; Genotype; Glycosaminoglycans; Growth Factor; Health; Heterotopic Ossification; Heterozygote; Histologic; Human; Human Genetics; Impaired wound healing; In Vitro; Inflammation; Injury; Iraq; Knock-out; Knockout Mice; Life; Link; Maintenance; Measures; Mental Depression; Methods; Military Personnel; Modeling; Molecular; Mus; Muscle; Musculoskeletal; Nature; Normalcy; Operative Surgical Procedures; Opiate Addiction; Orthopedic Surgery; Osteogenesis; Overdose; Pathologic; Pathway interactions; Patients; Phenotype; Plasminogen; Play; Predictive Factor; Predisposition; Production; Prosthesis; Radiation; Recovery; Replacement Arthroplasty; Risk; Role; Serum; Signal Transduction; Site; Spinal cord injury; Study models; Suicide; Tamoxifen; Therapeutic; Time; Tissues; Trauma; Ulcer; Up-Regulation; Veterans; Work; biobank; biomarker identification; bone; chondroitin sulfate glycosaminoglycan; chronic infection; chronic pain; circulating biomarkers; clinically relevant; collagenase; combat zone; comorbidity; diagnostic biomarker; experience; experimental study; healing; high risk; improved; in vivo; inhibitor; injured; insight; limb injury; liquid chromatography mass spectrometry; loss of function; military veteran; mouse model; musculoskeletal injury; novel therapeutic intervention; osteogenic; patient subsets; predictive tools; prevent; prophylactic; repaired; skeletal tissue; soft tissue; standard of care; targeted treatment; tissue repair; tomography; transcriptome sequencing; treatment strategy; wound healing

PROJECT SUMMARY Heterotopic ossification (HO) is the pathologic formation of ectopic bone in extra-skeletal tissues. Approximately 20% of patients who suffer some type of musculoskeletal injury develop HO. These injuries can be traumatic in nature or controlled tissue damage that occurs as a part of routine orthopaedic surgeries like joint replacement surgery or surgical amputations. The risk of HO disproportionately affects the Veteran population compared to civilians, especially due to higher risk of experiencing traumatic blast, brain, or spinal cord injury. Indeed, 64% of military blast injuries from the recent conflicts and Iraq and Afghanistan have resulted in HO. The presence of HO is associated with chronic pain, chronic infection, ulceration, impaired wound healing, and other related health complications. These complications from HO often preclude regaining mobility and function in the injured limb and substantially limit the use of prosthetics, impeding Veteran independence and return to duty or integration into civilian life. These difficulties can lead to opioid addiction, depression, and suicide, which are all major concerns to overall Veteran health. Current treatment options are limited due to the lack of understanding of the molecular mechanisms that drive ectopic bone formation during soft tissue healing following damage. Thus, the proposed work seeks to elucidate the mechanisms driving bone formation in HO in order to identify new, targeted therapeutic approaches for preventing and treating ectopic bone formation. The extracellular matrix (ECM) plays an essential role in regulating many biological processes including tissue repair and maintenance. While upregulated inflammation due to injury is known to significantly increase ECM synthesis, mechanisms linking aberrant ECM deposition to ectopic bone formation remain largely unexplored. We have carried out preliminary experiments in mouse models that consistently form ectopic bone that is histologically similar to HO in patients. Importantly, the soft tissue changes that are observed in these mice leading up to HO, particularly the aberrant and progressive accumulation of ECM molecules like collagens (COLs) and glycosaminoglycans (GAGs), closely recapitulate the changes observed in patients. Therefore, we hypothesize that abnormal overproduction of COL I and chondroitin sulfate (CS) GAGs creates an ECM environment capable of activating aberrant osteogenic signals in soft tissue in HO. The overall objective of this proposal is to elucidate the role of COL I and CS GAG accumulation in ectopic bone formation in order to identify potential therapeutic strategies and diagnostic markers using mouse models of HO. In Aim 1, we will determine the critical concentration and chemical composition of COL I and CS GAGs in the ECM that is able to establish a microenvironmental niche conducive for osteogenic differentiation and verify the concomitant upregulation of associated bone formation markers. In Aim 2, we will establish the inhibition of COL I and CS GAG accumulation as potential treatment strategies for inhibiting HO. In Aim 3, we will identify circulating biomarkers that may predict predisposition to HO and validate our findings from mouse model studies in deidentified human patient data through biorepository analyses to establish clinical relevance. The completion of these studies will establish direct links between excessive ECM accumulation and activation of bone formation in HO, paving the way for the development of new therapeutic strategies that can prevent ectopic bone growth by targeting mechanisms of ECM production. Furthermore, this work will provide critical, fundamental insights to our overall understanding of the role of ECM production in tissue repair following trauma, which will inform other important studies in fibrosis and wound healing to improve Veteran health.

项目摘要 异位骨化（HO）是指骨外组织中异位骨的病理形成。 大约20%的患有某种类型的肌肉骨骼损伤的患者发展为HO。这些损伤可以 是创伤性的，或者是作为常规骨科手术的一部分发生的可控组织损伤， 关节置换手术或手术截肢。HO的风险不成比例地影响退伍军人 与平民相比，特别是由于遭受创伤性爆炸、大脑或脊髓损伤的风险更高， 脊髓损伤事实上，在最近的冲突以及伊拉克和阿富汗战争中，64%的军事爆炸伤是由 结果是HO。HO的存在与慢性疼痛、慢性感染、溃疡形成、受损和/或炎症相关。 伤口愈合和其他相关的健康并发症。HO的这些并发症通常妨碍恢复 活动性和功能在受伤的肢体，并大大限制使用假肢，阻碍退伍军人 独立和重返岗位或融入平民生活。这些困难可能导致阿片类药物成瘾， 抑郁症和自杀，这些都是退伍军人健康的主要问题。目前的治疗方案是 由于缺乏对异位骨形成的分子机制的理解， 损伤后软组织愈合。因此，拟议的工作旨在阐明驱动 为了确定新的，有针对性的治疗方法，用于预防和治疗HO 异位骨形成细胞外基质（ECM）在调节许多生物学行为中起着重要作用。 包括组织修复和维护的过程。虽然已知由于损伤引起的炎症上调 显著增加ECM合成，将异常ECM沉积与异位骨形成联系起来的机制 大部分尚未开发。我们已经在小鼠模型中进行了初步实验， 形成组织学上与患者HO相似的异位骨。重要的是， 在这些导致HO的小鼠中观察到，特别是ECM的异常和进行性积累， 胶原蛋白（COL）和糖胺聚糖（GAG）等分子， 在病人身上。因此，我们假设I型胶原和硫酸软骨素（CS）的异常过量产生 GAG产生能够激活HO中软组织中异常成骨信号的ECM环境。的 本提案的总体目标是阐明COL I和CS GAG蓄积在异位妊娠中的作用。 骨形成，以确定潜在的治疗策略和诊断标志物， HO小鼠模型。在目标1中，我们将确定COL的临界浓度和化学组成 ECM中的I和CS GAG能够建立有利于成骨的微环境生态位， 分化和验证相关骨形成标志物的伴随上调。在目标2中，我们将 确立COL I和CS GAG积累的抑制作为抑制HO的潜在治疗策略。 在目标3中，我们将确定可能预测HO易感性的循环生物标志物，并验证我们的发现 从小鼠模型研究中，通过生物储存库分析， 临床相关性这些研究的完成将确立过度的企业内容管理与 HO中骨形成的积累和激活，为开发新的治疗方法铺平了道路 通过靶向ECM产生机制来预防异位骨生长的策略。此外，委员会认为， 这项工作将为我们全面理解ECM生产在以下方面的作用提供关键的、基本的见解： 创伤后的组织修复，这将为纤维化和伤口愈合的其他重要研究提供信息， 改善退伍军人健康。

项目成果

Inhibition of nucleotide biosynthesis disrupts lipid accumulation and adipogenesis.

• DOI: 10.1016/j.jbc.2023.104635
• 发表时间: 2023-05
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Shinde, Abhijit B.;Nunn, Elizabeth R.;Wilson, Genesis A.;Chvasta, Mathew T.;Pinette, Julia A.;Myers, Jacob W.;Peck, Sun H.;Spinelli, Jessica B.;Zaganjor, Elma
• 通讯作者: Zaganjor, Elma