Mechanisms Underlying Heterotopic Ossification

 描述(申请人提供)：异位骨化的机制异位骨化(HO)是正常骨骼系统之外的真正的骨形成。HO的确切机制尚不清楚，尽管已经涉及到许多局部和系统的信号通路和细胞成分。我们以前的工作表明，神经炎性因子P物质(SP)与肥大细胞和巨噬细胞一起调节失调，导致骨形态发生蛋白(BMP)信号升高，从而触发病理过程。表达Glast和Tie2的间充质干/祖细胞(MSCs)对诱导信号作出反应，通过软骨内成骨形成异位骨。我们的中心假设是，与正常的骨骼形成不同，HO的过程是一种损伤/炎症诱导的、异常的局部形态发生现象。具体地说，多种疾病特异性致病因素，包括细胞和细胞外分子元件，相互协调，形成一个独特的分层微环境，类似于内源干细胞生态位，以诱导和繁殖HO。在生态位中，从局部组织中招募的MSCs是HO的起源细胞，特定的局部支持细胞(如局部神经、肥大细胞)和分子(如SP)成分对于调控这些MSCs的刻板印象的自我更新、增殖、成软骨和成骨分化至关重要。因此，治疗方法的发展必须考虑局部神经支配和肥大细胞的作用，以及HO起源的细胞的局部来源。这需要一种跨学科的方法来研究作为最低功能单元的生态位，这是本提案的目标。了解HO来源细胞的特征对于精确的靶向治疗是必要的 预防或限制这种紊乱。拟议研究的第一部分将研究直接参与HO的生态位栖息细胞。第二部分将研究启动和繁殖HO的生态位支持细胞和关键分子成分。一个主要的焦点将是研究通过抑制在HO生态位中发挥核心作用的因子，如SP，来预防或限制HO的治疗效果。因此，总体目标是开发一种治疗这种衰弱障碍的方法，目前还没有有效的治疗方法。

 DESCRIPTION (provided by applicant): Mechanisms Underlying Heterotopic Ossification Heterotopic ossification (HO) is bona fide bone formation outside of the normal skeletal system. The precise mechanisms underlying HO are unknown, although numerous signaling pathways and cellular components, local and systemic, have been implicated. Our previous work demonstrated that dysregulation of the neuroinflammatory factor, substance P (SP), along with mast cells and macrophages, leads to elevated bone morphogenetic protein (BMP) signaling that triggers the pathological process. Glast and Tie2 expressing mesenchymal stem/progenitor cells (MSCs) respond to the inductive signals and form ectopic bone through endochondral ossification. Our central hypothesis is that unlike normal skeletogenesis, the process of HO is an injury/inflammation induced, abnormal local morphogenic phenomenon. Specifically, multiple disease specific contributing factors, including both cellular and extracellular molecular elements, co-ordinate with each other to form a unique hierarchical microenvironment, similar to endogenous stem cells niches, to induce and propagate HO. In the niche, MSCs recruited from local tissues are the cells of origin of HO, and specific local supportive cellular (e.g. local neres, mast cells) and molecular (e.g. SP) components are crucial to regulate the stereotyped self-renewal, proliferation, chondrogenic and osteogenic differentiation of these MSCs. Thus development of therapeutic approaches must consider the role of the local innervation and mast cells as well as local sources of cells of origin of HO. This requires an interdisciplinary approac to study the niche as a minimum functional unit, the goal of this proposal. Understanding the characteristics of the cells of origin of HO will be necessary for precise therapeutic targeting to prevent or limit the disorder. The first part of the proposed studies will examine the niche dwelling cells that directly participate in HO. The second part will study the niche supportive cells and key molecular components that initiate and propagate HO. A major focus will be to examine the therapeutic effectiveness in preventing or limiting HO by inhibiting factors, such as SP, that play a central role in the HO niche. Thus the overall goal is to develop a therapy for thi debilitating disorder for which there currently is no effective treatment.