Molecular and cellular mechanisms of heterotopic ossification

异位骨化的分子和细胞机制

• 批准号: 7993157
• 负责人: PAUL B YU
• 金额: $ 39.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993157
• 关键词: ACVR1 gene; Address; Adoptive Transfer; Affect; Autoimmune Process; Blood Vessels; Bone Marrow; Bone Morphogenetic Proteins; Cardiac; Cells; Complement; Connective Tissue; Development; Disease; Fascia; Fracture; Gene Expression; Genetic; Grant; Heterotopic Ossification; Human; Immune; Inflammation; Injury; Joints; Lead; Lesion; Ligands; Mediating; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Muscle; Mutation; Natural regeneration; Operative Surgical Procedures; Osteogenesis; Pain; Pericytes; Population; Process; Proteins; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal Muscle Satellite Cells; Stem cells; Stimulus; Syndrome; Techniques; Testing; Trauma; Vascular Diseases; base; bone; bone morphogenetic protein receptor type I; cellular targeting; effective therapy; human disease; injury and repair; insight; mouse model; mutant; novel; novel strategies; osteogenic; osteoprogenitor cell; progenitor; programs; progressive myositis ossificans; public health relevance; repaired; soft tissue

DESCRIPTION (provided by applicant): Heterotopic ossification (HO), the formation of ectopic endochondral bone in skeletal muscle and soft tissues, is a significant cause of morbidity from joint immobility and pain. The precise mechanisms responsible for HO are not known; however, its association with postsurgical and posttraumatic contexts suggests a process of disordered injury repair. Further insights into the causes of HO may be gained from a congenital HO syndrome, fibrodysplasia ossificans progressiva (FOP). FOP is caused by "constitutively-activating" mutations in the bone morphogenetic protein (BMP) type I receptor ALK2, which result in progressive and widespread joint ossifications triggered by minimal trauma or inflammation. Both FOP and acquired forms of HO lack effective therapies. In fact, there is significant evidence that both FOP and HO are caused by inappropriate activation of the BMP signaling pathway. It is not known how enhanced BMP signaling deviates the injury repair program, or which populations of cells mediate the effects of enhanced BMP signaling. To address these questions we have developed a mouse model of FOP in which a constitutively-active mutant form of ALK2 (caALK2) is inducibly expressed. Similar to affected humans, expression of this gene does not spontaneously induce HO, but vigorous ossification and joint fusion occur with additional stimuli of inflammation and muscle injury. Our subsequent studies with this model suggest that these caALK2 proteins may not be constitutively-active, as previously thought, but may sensitize cells to traditional ligand-mediated BMP signals. In Aim 1 of this grant, we will employ this model to discern the mechanisms by which caALK2 sensitizes cells to BMP signals, testing whether caALK2 requires ligand-mediated signaling or functions independently. To identify the cellular progenitors which mediate the effects of enhanced BMP signaling, and which contribute to the ectopic bone lesions, in Aim 2 we have targeted the expression of mutant caALK2 to several candidate progenitor lineages. Using a complement of cell-based, genetic targeting, and adoptive transfer techniques, we will systematically determine the impact of expressing caALK2 in compartments with known osteogenic potential, including skeletal muscle satellite cells, vascular pericytes, as well as bone-marrow derived lineages. In Aim 3, we examine the role of innate immune signaling in the development of ectopic bone in this model. Understanding how caALK2 mutations alter the consequences of BMP signaling could highlight novel molecular or cellular targets for management of HO. This proposal seeks to elucidate how enhanced BMP signaling impacts mesenchymal progenitors and governs adaptive and maladaptive osteogenesis at the interface of injury, inflammation, and regeneration. PUBLIC HEALTH RELEVANCE: This proposal asks how bone morphogenetic protein signals, which normally regulate the activity of progenitor cells involved in the repair of muscle, blood vessels, connective tissues, and bone, may become dysregulated to cause inappropriate bone formation in the human diseases of heterotopic ossification and fibrodysplasia ossificans progressiva. In addition to providing insights into the mechanism of these poorly understood processes, these studies may identify much needed novel approaches for their management. These mechanisms have relevance to a broader set of conditions in which inflammation and injury appear to lead to abnormal ossification in autoimmune, cardiac, and vascular disease.

描述（由申请方提供）：异位骨化（HO），即骨骼肌和软组织中异位软骨内骨的形成，是关节不动和疼痛导致发病的重要原因。HO的确切机制尚不清楚;然而，其与手术后和创伤后环境的相关性表明了一个无序的损伤修复过程。进一步了解HO的原因可能是从先天性HO综合征，进行性骨化性纤维发育不良（FOP）。FOP是由骨形态发生蛋白（BMP）I型受体ALK 2中的“组成性激活”突变引起的，其导致由最小创伤或炎症触发的进行性和广泛的关节骨化。FOP和获得性HO都缺乏有效的治疗方法。事实上，有重要证据表明FOP和HO都是由BMP信号通路的不适当激活引起的。目前尚不清楚增强的BMP信号传导如何偏离损伤修复程序，或者哪些细胞群体介导增强的BMP信号传导的作用。为了解决这些问题，我们开发了FOP的小鼠模型，其中ALK 2的组成型活性突变形式（caALK 2）被诱导表达。与受影响的人类相似，该基因的表达不会自发诱导HO，但在炎症和肌肉损伤的额外刺激下会发生剧烈的骨化和关节融合。我们随后对该模型的研究表明，这些caALK 2蛋白可能不像以前认为的那样具有组成性活性，但可能使细胞对传统配体介导的BMP信号敏感。在本研究的目标1中，我们将利用该模型来识别caALK 2使细胞对BMP信号敏感的机制，测试caALK 2是否需要配体介导的信号传导或独立发挥作用。为了鉴定介导增强的BMP信号传导的作用并且有助于异位骨病变的细胞祖细胞，在目的2中，我们将突变体caALK 2的表达靶向于几种候选祖细胞谱系。使用基于细胞的基因靶向和过继转移技术的补充，我们将系统地确定在具有已知成骨潜力的隔室中表达caALK 2的影响，包括骨骼肌卫星细胞、血管周细胞以及骨髓来源的谱系。在目的3中，我们研究了先天免疫信号在该模型中异位骨发育中的作用。了解caALK 2突变如何改变BMP信号传导的结果可以突出HO管理的新分子或细胞靶点。该提案旨在阐明增强的BMP信号传导如何影响间充质祖细胞，并在损伤，炎症和再生的界面处控制适应性和适应不良的骨生成。 公共卫生相关性：该提案询问骨形态发生蛋白信号如何在正常情况下调节参与肌肉、血管、结缔组织和骨修复的祖细胞的活性，可能变得失调，从而导致异位骨化和进行性骨化性纤维发育不良等人类疾病中的不适当骨形成。除了提供对这些知之甚少的过程的机制的见解之外，这些研究还可以确定急需的新方法来进行管理。这些机制与一系列更广泛的疾病相关，其中炎症和损伤似乎导致自身免疫性疾病、心脏病和血管疾病中的异常骨化。