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: 10368380
• 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/10368380
• 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; Conflict (Psychology); Data; Deposition; Depression and Suicide; Development; Direct Lytic Factors; Environment; Excision; Extracellular Matrix; Fibrosis; Gene Expression; Genetic; Genotype; Glycosaminoglycans; Growth Factor; Health; Heterotopic Ossification; Histologic; Human; Human Genetics; Impaired wound healing; In Vitro; Inflammation; Injury; Iraq; Knock-out; Knockout Mice; Lead; 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; Rogaine; Role; Serum; Signal Transduction; Site; Spinal cord injury; Study models; Suicide; Tamoxifen; Therapeutic; Time; Tissues; Trauma; Ulcer; Up-Regulation; Veterans; Work; biobank; 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; 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）是骨骼外组织异位骨的病理形成。 大约有20％的患者患有某种类型的肌肉骨骼损伤。这些伤害可以 在自然界或受控的组织损伤中是常规骨科手术的一部分发生的创伤性损害 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，人口相比，尤其是由于较高的创伤性爆炸，大脑或脊柱的风险 绳索受伤。确实，最近发生的冲突中有64％的军事爆炸受伤，伊拉克和阿富汗 导致HO。 HO的存在与慢性疼痛，慢性感染，溃疡，受损有关 伤口愈合和其他相关的健康并发症。这些并发症通常无法恢复 受伤的肢体中的流动性和功能，并实质上限制了假肢的使用，阻碍了退伍军人 独立并恢复职责或融入平民生活。这些困难会导致阿片类药物成瘾， 抑郁症和自杀，这都是整体退伍军人健康的主要关注点。当前的治疗选择是 由于缺乏对驱动异位骨形成的分子机制的了解而受到限制 损伤后软组织愈合。因此，拟议的工作旨在阐明驾驶机制 HO中的骨形成是为了识别预防和治疗的新的，有针对性的治疗方法 异位骨形成。细胞外基质（ECM）在调节许多生物学方面起着至关重要的作用 包括组织修复和维护在内的过程。虽然已知因受伤引起的炎症上调 显着增加了ECM合成，将异常ECM沉积与异位骨形成联系起来的机制 在很大程度上尚未探索。我们已经在始终如一的小鼠模型中进行了初步实验 在组织学上与患者的HO相似的异位骨。重要的是，软组织变化是 在这些导致HO的小鼠中观察到，尤其是ECM的异常和渐进式积累 分子（例如胶原蛋白（COLS）和糖胺聚糖（GAG））紧密概括了观察到的变化 在患者中。因此，我们假设Col I和硫酸软骨素（CS）异常过量生产 插科打s创建了一个ECM环境，能够在HO中的软组织中激活异常的成骨信号。这 该提案的总体目的是阐明Col I和CS GAG积累在异位中的作用 骨形成以确定潜在的治疗策略和诊断标记 HO的鼠标模型。在AIM 1中，我们将确定Col的临界浓度和化学成分 ECM中的I和CS GAG能够建立有利于成骨的微环境利基市场 分化并验证相关骨形成标记的同时上调。在AIM 2中，我们将 建立对Col I和CS GAG积累的抑制作用，作为抑制HO的潜在治疗策略。 在AIM 3中，我们将确定循环的生物标志物可能预测易感性并验证我们的发现 通过通过生物验证分析在死识别的人类患者数据中进行的小鼠模型研究以建立 临床相关性。这些研究的完成将建立过度ECM之间的直接联系 HO中骨形成的积累和激活，为开发新治疗铺平了道路 可以通过靶向ECM生产机制来预防异位骨生长的策略。此外， 这项工作将为我们对ECM生产在 创伤后的组织修复，这将为纤维化和伤口愈合方面的其他重要研究提供信息 改善退伍军人健康。