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.

项目概要 异位骨化（HO）是骨骼外组织中异位骨的病理形成。 大约 20% 遭受某种类型肌肉骨骼损伤的患者会出现 HO。这些伤害可以 本质上是创伤性的，或者是常规骨科手术中发生的受控组织损伤，例如 关节置换手术或截肢手术。 HO 的风险对退伍军人的影响尤为严重 与平民相比，特别是由于经历创伤性爆炸、脑部或脊髓损伤的风险更高 脊髓损伤。事实上，近期冲突以及伊拉克和阿富汗造成的军事爆炸伤中，有 64% 导致 H2O。 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。 HO 的这些并发症通常会妨碍患者康复 受伤肢体的活动能力和功能，大大限制了假肢的使用，阻碍了退伍军人 独立并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，这些都是退伍军人整体健康的主要问题。目前的治疗方案是 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 软组织损伤后愈合。因此，拟议的工作旨在阐明驱动机制 HO 中的骨形成，以确定新的、有针对性的预防和治疗方法 异位骨形成。细胞外基质（ECM）在调节许多生物体中发挥着重要作用 过程包括组织修复和维护。虽然众所周知，由于受伤而导致的炎症上调 显着增加 ECM 合成，异常 ECM 沉积与异位骨形成之间的联系机制 很大程度上仍未被探索。我们已经在小鼠模型中进行了初步实验，结果一致 形成异位骨，组织学上与患者体内的 HO 相似。重要的是，软组织的变化 在导致 HO 的这些小鼠中观察到，特别是 ECM 的异常和进行性积累 胶原蛋白 (COL) 和糖胺聚糖 (GAG) 等分子密切概括了观察到的变化 在患者中。因此，我们推测 COL I 和硫酸软骨素 (CS) 的异常过量产生 GAG 创建了一个 ECM 环境，能够激活 HO 中软组织中的异常成骨信号。这 该提案的总体目标是阐明 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 的临界浓度和化学成分 ECM 中的 I 和 CS GAG 能够建立有利于成骨的微环境生态位 分化并验证相关骨形成标志物的伴随上调。在目标 2 中，我们将 建立抑制 COL I 和 CS GAG 积累作为抑制 HO 的潜在治疗策略。 在目标 3 中，我们将识别可预测 HO 易感性的循环生物标志物并验证我们的发现 通过生物样本库分析对未识别的人类患者数据进行小鼠模型研究，以建立 临床相关性。这些研究的完成将建立过量 ECM 之间的直接联系 H2O 中骨形成的积累和激活，为新疗法的开发铺平了道路 通过针对 ECM 产生机制来预防异位骨生长的策略。此外， 这项工作将为我们全面了解 ECM 生产在 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。