Tendon-dependent Control of Longitudinal Bone Growth

纵向骨生长的肌腱依赖性控制

• 批准号: 9975714
• 负责人: Francesco B Ramirez
• 金额: $ 37.29万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975714
• 关键词: Acute; Animals; Anterior; Architecture; Binding; Biological; Biology; Biomechanics; Bone Growth; Bone Lengthening; Cell Culture Techniques; Cell Differentiation process; Cells; Cellular Structures; Chest; Clinical; Clinical Management; Collagen Fibril; Computer Analysis; Connective Tissue Diseases; Data; Disease; Elastic Fiber; Elements; Epiphysial cartilage; Event; Extracellular Matrix; Extracellular Matrix Proteins; FBN1; Functional disorder; Gene Expression; Genes; Genetic; Growth; Health; Homeostasis; Hyperactive behavior; Impairment; Injury; Investigation; Knowledge; Life; Ligaments; Limb structure; Marfan Syndrome; Mathematics; Measures; Mechanical Stress; Mechanics; Medical; Membrane; Modeling; Molecular; Molecular Abnormality; Molecular Structure; Morphology; Mus; Muscle; Musculoskeletal; Musculoskeletal Diseases; Mutant Strains Mice; Mutate; Natural History; Newborn Infant; Osteogenesis; Pathology; Patients; Pharmacology; Pharmacotherapy; Physical condensation; Physiologic Ossification; Physiology; Play; Process; Property; Proteins; Protocols documentation; Research; Research Design; Research Project Grants; Role; Severities; Signal Pathway; Signal Transduction; Site; Solid; Specific qualifier value; Statistical Models; Stress; Structural defect; Structure; Tendon structure; Testing; Thromboplastin; Time; Tissues; Transforming Growth Factor beta; Translating; Treatment Efficacy; Vertebral column; base; bone; calcification; differential expression; disease-causing mutation; experimental study; gene product; improved; in vivo; innovation; insight; limb bone; malformation; mechanical force; mechanical properties; neutralizing antibody; physical property; postnatal; protein expression; public health relevance; receptor binding; skeletal; skeletal tissue; stem; stem cells; tendon development; tissue degeneration

 DESCRIPTION (provided by applicant): A disproportionate increase of longitudinal bone growth that causes serious malformations of the limbs, anterior chest and spine is the clinical hallmark of patients afflicted with Marfan syndrome (MFS), a connective tissue disease caused by mutations in the extracellular matrix (ECM) protein and TGFβ regulator fibrillin-1. Our preliminary studies of mice with tissue-specific ablated Fbn1 gene activity have revealed an unsuspected causal relationship between tendon/ligament (T/L) dysfunction and longitudinal bone overgrowth (LBO). Specifically, we found that (1) Fbn1 inactivation in T/L cells was necessary and sufficient to promote linear bone overgrowth associated with dysregulated growth plate (GP) gene expression; (2) fibrillin-1-deficient tendons displayed abnormal tissue architecture and impaired mechanical properties, particularly at bone- insertion sites; (3) the relative amount of fibrillin-1 correlated with discrete changes in tendon mechanics; (4) tendon-derived stem/progenitor cell (TSPC) cultures deficient for fibrillin-1 differentiated improperly as result of increased latent TGFβ activation; and (5) ectopic tendon calcification of fibrillin-1-deficient tendons was commonly observed. We therefore hypothesize that fibrillin-1 assemblies normally restrict GP-driven linear growth of neighboring bones by specifying the mechanical properties of tendons through the control of ECM organization and TGF-regulated TSPC differentiation. Accordingly, the scope of our proposal is two-fold; first, to characterize how fibrillin-1 deficiency translates into tendon dysfunction and tendon-associated LBO, and second, to establish how local TGF hyperactivity in tendons promote tissue degeneration thereby leading to excessive linear growth of the adjacent, structurally normal bones. To this end, we will characterize the expression of molecular and cellular determinants of tendon development and maturation in mice deficient for fibrillin-1 in T/L matrices, in addition to employing computational approaches to identify probable disease-causing molecular abnormalities in the GP of these tendon-defective animals (Aim 1); apply data-driven statistical models to determine how graded fibrillin-1 deficiencies correlate with tendon mechanics and associated LBO (Aim 2); and assess whether systemic TGFβ neutralization modifies tendon pathology and LBO severity in fibrillin-1-deficient mice (Aim 3). The results of these investigations are expected to substantially advance our limited understanding of tendon function in health and disease and implicitly, of the cellular, molecular and tissue factors that coordinate the postnatal growth of musculoskeletal tissues.

 描述（由申请人提供）：纵向骨生长不成比例的增加，导致四肢、前胸和脊柱严重畸形，是马凡综合征（MFS）患者的临床特征，马凡综合征是一种由细胞外突变引起的结缔组织疾病。我们对具有组织特异性消融 Fbn1 基因活性的小鼠进行的初步研究揭示了基质 (ECM) 蛋白和 TGFβ 调节因子 fibrillin-1 之间的因果关系。具体来说，我们发现（1）T/L 细胞中 Fbn1 失活对于促进与生长板（GP）基因失调相关的线性骨过度生长是必要且充分的。 (2) fibrillin-1 缺陷肌腱表现出异常的组织结构和受损的机械性能，特别是在骨插入部位；(3) fibrillin-1 的相对量与肌腱力学的离散变化相关；缺乏 fibrillin-1 的肌腱干细胞/祖细胞 (TSPC) 培养物无法正确分化为 潜在 TGFβ 激活增加的结果；(5) 通常观察到 fibrillin-1 缺陷肌腱的异位肌腱钙化，因此我们发现 fibrillin-1 组件通常通过指定肌腱的机械特性来限制 GP 驱动的邻近骨骼的线性生长。通过控制 ECM 组织和 TGF 调节 TSPC 分化，我们的建议有两个范围：首先，描述 fibrillin-1 缺陷的特征。转化为肌腱功能障碍和肌腱相关的 LBO，其次，确定肌腱中局部 TGFβ 过度活跃如何促进组织退化，从而导致邻近结构正常的骨骼过度线性生长。为此，我们将表征分子的表达。 T/L 基质中缺乏 fibrillin-1 的小鼠中肌腱发育和成熟的细胞决定因素，此外还采用计算方法来识别这些肌腱缺陷的 GP 中可能引起疾病的分子异常动物（目标 1）；应用数据驱动的统计模型来确定 fibrillin-1 缺陷的分级与肌腱力学和相关 LBO 的相关性（目标 2）；并评估全身性 TGFβ 中和是否会改变 fibrillin-1 缺陷的肌腱病理学和 LBO 严重程度小鼠（目标 3）预计这些研究的结果将大大推进我们对健康和疾病中肌腱功能的有限理解，以及对协调产后肌腱功能的细胞、分子和组织因素的理解。肌肉骨骼组织的生长。

项目成果

The influence of fibrillin-1 and physical activity upon tendon tissue morphology and mechanical properties in mice.

fibrillin-1 和体力活动对小鼠肌腱组织形态和机械性能的影响。

• 发表时间: 2019
• 影响因子: 2.5
• 作者: Tran, Peter H T;Skrba, Tanja;Wondimu, Elisabeth;Galatioto, Giuseppina;Svensson, René Brüggebusch;Olesen, Annesofie T;Mackey, Abigail L;Magnusson, S Peter;Ramirez, Francesco;Kjaer, Michael
• 通讯作者: Kjaer, Michael

Fibrillin-1 deficiency in the outer perichondrium causes longitudinal bone overgrowth in mice with Marfan syndrome.

外软骨膜中的 Fibrillin-1 缺乏会导致马凡氏综合征小鼠纵向骨过度生长。

• 发表时间: 2022-09-29
• 影响因子: 3.5
• 作者: Sedes, Lauriane;Wondimu, Elisa;Crockett, Brittany;Hansen, Jens;Cantalupo, Anna;Asano, Keiichi;Iyengar, Ravi;Rifkin, Daniel B;Smaldone, Silvia;Ramirez, Francesco
• 通讯作者: Ramirez, Francesco