Targeting jmjd3 mitigates heterotopic ossification

项目总结/摘要 异位骨化（HO）是一种骨外骨化的病理形成， 炎性损伤，约20%的患者在髋关节置换术、烧伤或肌肉骨骼损伤后发生。 目前，没有治疗或物理治疗为基础的协议存在，以预防或治疗HO。在这方面， 在我们理解HO形成和进展的分子机制方面是一个空白。 我们提供的数据表明，HO巨噬细胞（Mφ）中组蛋白去甲基化酶JMJD 3的表达增加， 在HO损伤部位持续产生转化生长因子β（TGF β 1）。这些过量的TGF β 1 引起异常的间充质祖细胞（MPC）骨软骨骨化，导致HO形成。 此外，使用人细胞和我们的实验性临床相关的HO鼠模型，我们已经确定， 干扰素-β（IFNβ），通过Janus激酶（JAK）/信号转导和转录激活因子（STAT） 机制诱导Mφ中的JMJD 3。这些结果导致我们的中心假设，IFN γ/JAK/STAT 3 信号直接增加HO组织巨噬细胞中Jmjd 3的表达，并且JMDJ 3增加巨噬细胞 Tgfb 1表达从而促进异常MPC命运和HO形成。我们进一步假设Mφ特异性 JAK 1/3或JMJD 3的抑制，因此，使用新型靶向纳米疗法的TGF β 1产生将停止HO 形成和发展。因此，我们提出了以下目的：目的1：阐明IFN γ 1/JAK 1/STAT 3- 介导的机制，调节人和小鼠HO伤口中Mφ特异性JMJD 3表达。目标二： 明确创伤Mφ JMJD 3对TGF β 1表达的调节以及Mφ JMJD 3对TGF β 1表达的旁分泌作用。 MPC在体内正常和异常伤口愈合（HO）条件下的命运。目的3：检测Mφ特异性 以及靶向Mφ的JMJD 3和JAK 1/3纳米颗粒对MPC表型的治疗功效和时机， HO编队。在这个转化项目中，我们的数据将为开发有前途的预防性药物铺平道路。 针对介导Mφ调节的表观遗传酶的细胞特异性靶向的抗肿瘤剂， MPC命运，从而防止损伤后HO的发展。

PROJECT SUMMARY/ABSTRACT Heterotopic ossification (HO) is the pathologic formation of extra-skeletal that is always preceded by an inflammatory insult and occurs in ~20% of patients after hip arthroplasty, burns or musculoskeletal injury. Currently, no therapeutics or physical therapy-based protocols exist to prevent or treat HO. In this regard, there is a void in our understanding of the molecular mechanisms underlying HO formation and progression. We present data that the histone demethylase, JMJD3, is increased in HO macrophages (Mφs) resulting in persistent production of transforming growth factor-beta (TGFꞵ1) at the HO injury site. This excess TGFꞵ1 causes aberrant mesenchymal progenitor cell (MPC) osteochondral ossification, resulting in HO formation. Further, using human cells and our experimental clinically relevant murine models of HO, we have identified that interferon-beta (IFNβ), via a janus kinase (JAK) / signal transducer and activator of transcription (STAT) mechanism induces JMJD3 in Mφs. These results have led to our central hypothesis that IFNꞵ/JAK/STAT3 signaling directly increases Jmjd3 expression in HO tissue macrophages and that JMDJ3 increases macrophage Tgfb1 expression thus promoting aberrant MPC fate and HO formation. We further postulate that Mφ specific repression of JAK1/3 or JMJD3 and thus, TGFꞵ1 production using a novel targeted nanotherapy will halt HO formation and progression. As such, we propose the following aims: Aim 1: Elucidate the IFNꞵ1/JAK1/STAT3- mediated mechanism that regulates Mφ-specific JMJD3 expression in human and mouse HO wounds. Aim 2: Define the regulation of wound Mφ JMJD3 on TGFꞵ1 expression and the paracrine effects of Mφ JMJD3 on MPC fate under conditions of normal and aberrant wound healing (HO) in vivo. Aim 3: Examine the Mφ specificity and therapeutic efficacy and timing of Mφ-targeted JMJD3 and JAK1/3 nanoparticles on MPC phenotype and HO formation. In this translational project, our data will pave the way for the development of promising preventive nanotherapeutic agents aimed at cell-specific targeting of epigenetic enzymes that mediate Mφ regulation of MPC fate and thereby prevent HO development following injury.