Mechano signals regulating tendon and ligament homeostasis

机械信号调节肌腱和韧带稳态

• 批准号: 10707502
• 负责人: HIROSHI ASAHARA
• 金额: $ 39.05万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707502
• 关键词: Address; African; African American population; Age; Aging; Agonist; Biomechanics; Cartilage; Data; Development; Elasticity; Erythrocytes; Exercise; Gene Expression; Gene Expression Profiling; Genes; Genetic Research; Hereditary Disease; Histologic; Homeostasis; Human; Immobilization; Injury; Ion Channel; Kinetics; Knock-in; Ligaments; Malaria; Mechanical Stimulation; Mediating; Medical; Modeling; Molecular; Morphology; Motor; Movement; Mus; Muscle; Muscle Contraction; Musculoskeletal Diseases; Musculoskeletal System; Mutation; Organ; Pathologic; Performance; Phenotype; Physical Performance; Physiologic Ossification; Physiological; Physiology; Piezo 1 ion channel; Play; Property; Reporting; Resistance; Role; Signal Transduction; Small Interfering RNA; Speed; Stretching; Structure; Sum; Tendon structure; Testing; Tissues; Translating; Up-Regulation; Variant; Wild Type Mouse; aged; biomechanical test; bone; comparison control; gain of function; gain of function mutation; improved; in vivo; innovation; insight; knock-down; ligament development; ligament injury; loss of function; mature animal; mechanical stimulus; mechanotransduction; molecular phenotype; novel; postnatal; response; small molecule; therapeutic target; transcriptome; transmission process; treadmill; viscoelasticity

ABSTRACT Mechano-stimulation in the musculoskeletal system plays a major role in the homeostasis of all tissues and organs. Particularly in tendons, the proper physiologic exercise load has an anabolic effect with increased tenogenic gene expression in humans; however, the molecular mechanisms that sense mechanical stimuli remain unclear. Piezo1 is a mechano-sensitive ion channel involved in mechano-sensing in various organs and tissues; however, it has not yet been examined in tendons or ligaments. In mice, the R2482H mutation of Piezo1 is an active form mimicking a gain-of-function (GOF) PIEZO1 variant found in humans. To test the potential effects of Piezo1 in physical performance, we generated systemic GOF Piezo1 (Piezo1systemic-GOF) mice, muscle-specific GOF Piezo1 (Piezo1muscle-GOF) mice, and tendon-specific GOF Piezo1 (Piezo1tendon-GOF) mice and found that the jumping power of Piezo1tendon-GOF mice as well as Piezo1systemic-GOF mice at 12-weeks- old was ~1.6 times greater than in both wild-type mice and Piezo1muscle-GOF mice. Consistent with this, significantly altered macroscopic and histological phenotypes were observed in the tendons of Piezo1tendon-GOF mice with increased tendon-specific gene expression. We also found that upregulation of aging related ossification gene expression was significantly reduced in aged Piezo1tendon-GOF mice. This suggests that constitutively enhanced PIEZO1 activity promotes physical performance via tendons/ligaments. These preliminary data underlie our hypothesis that PIEZO1 acts as a critical mechano-sensor in tenocytes, maintaining and promoting tendon/ligament functions by orchestrating tendon/ligament-specific gene expression. To test this hypothesis, we will pursue the following Aims: Aim 1: Analyze the function of Piezo1 in human and mouse tendon homeostasis and aging. We will examine the function of Piezo1 in tenocytes for tendon homeostasis and in aging by morphological, histological and gene expression analysis of tendons from Piezo1tendon-GOF mice and tendon specific loss of function (LOF) Piezo1 (Piezo1tendon-LOF) mice at different aging points. We will also test the role of PIEZO1 in human tenocytes by transcriptome analysis with PIEZO1 siRNA knockdown or a small molecule PIEZO1 activator. Aim 2: Evaluate the role of Piezo1 in tenocytes on physiological performance and exercise in mice. We will evaluate the role of Piezo1 in tenocytes to potentiate physical performance using postnatally induced tendon specific gain of function and loss of function Piezo1 mice at different ages. Thereafter, we will examine whether this physical ability could be strengthened by physiological exercise inducing anabolic mechanical stimulation. Aim 3: Analyze the biomechanical properties of tendon that are regulated by Piezo1. We will uncover how the kinetic energy for the enhanced jumping ability of the Piezo1tendon-GOF mouse is produced by biomechanical analysis of tendon stored energy and muscle contraction power. Completion of these aims will support the concept that Piezo1 could be a therapeutic target to maintain or enhance structure and function of the musculoskeletal system.

摘要 肌肉骨骼系统中的机械刺激在所有组织的稳态中起着重要作用， 机关特别是在肌腱中，适当的生理运动负荷具有合成代谢作用， 人类tenogenic基因表达;然而，感知机械刺激的分子机制 仍然不清楚。Piezo 1是一种机械敏感离子通道，参与各种器官中的机械传感， 组织;然而，尚未在肌腱或韧带中进行检查。在小鼠中， Piezo 1是一种活性形式，模拟在人类中发现的功能获得性（GOF）PIEZO 1变体。测试 Piezo 1在物理性能方面的潜在影响，我们产生了系统GOF Piezo 1（Piezo 1 systemic-GOF） 小鼠、肌肉特异性GOF Piezo 1（Piezo 1 muscle-GOF）小鼠和肌腱特异性GOF Piezo 1（Piezo 1 tendon-GOF） 小鼠，并发现Piezo 1 tendon-GOF小鼠以及Piezo 1 systemic-GOF小鼠在12周时的跳跃能力- 年龄是野生型小鼠和Piezo 1 muscle-GOF小鼠的1.6倍。与此相一致， 在Piezo 1 tendon-GOF的肌腱中观察到显著改变的宏观和组织学表型 肌腱特异性基因表达增加的小鼠。我们还发现，衰老相关的上调 骨化基因表达在老年Piezo 1 tendon-GOF小鼠中显著降低。这表明 组成性增强的PIEZO 1活性通过肌腱/韧带促进身体表现。这些 初步数据支持我们的假设，即PIEZO 1在腱细胞中充当关键的机械传感器， 通过协调肌腱/韧带特异性基因维持和促进肌腱/韧带功能 表情为了验证这一假设，我们将追求以下目标：目标1：分析 Piezo 1在人类和小鼠肌腱稳态和衰老中的作用。我们将研究Piezo 1在 肌腱细胞的形态学、组织学和基因表达分析 来自Piezo 1 tendon-GOF小鼠的肌腱和肌腱特异性功能丧失（LOF）Piezo 1（Piezo 1 tendon-LOF）小鼠， 不同的老化点。我们还将通过转录组分析测试PIEZO 1在人腱细胞中的作用， PIEZO 1 siRNA敲低或小分子PIEZO 1激活剂。目的2：评估Piezo 1在以下方面的作用： 肌腱细胞对小鼠生理性能和运动的影响。我们将评估Piezo 1在以下方面的作用： 腱细胞，以利用出生后诱导的腱特异性功能增益来增强身体性能， 不同年龄的Piezo 1小鼠功能丧失。之后，我们将研究这种物理能力是否可以 通过生理锻炼诱导合成代谢机械刺激而加强。目标3：分析 肌腱的生物力学特性由Piezo 1调节。我们将揭示动能是如何 Piezo 1 tendon-GOF小鼠的跳跃能力增强是通过肌腱的生物力学分析产生的 储存能量和肌肉收缩力。这些目标的完成将支持Piezo 1 可能是维持或增强肌肉骨骼系统结构和功能的治疗靶点。

项目成果

The essential role of Mkx in periodontal ligament on the metabolism of alveolar bone and cementum.

• DOI: 10.1016/j.reth.2023.12.007
• 发表时间: 2024-03
• 期刊: REGENERATIVE THERAPY
• 影响因子: 4.3
• 作者: Yagasaki, Lisa;Chiba, Tomoki;Kurimoto, Ryota;Nakajima, Mitsuyo;Iwata, Takanori;Asahara, Hiroshi
• 通讯作者: Asahara, Hiroshi