Defining the role of the iron-sensor Tfr2 in ossification processes

异位骨化（HO）是指异常解剖部位的骨化过程。这是全髋关节置换术后常见的严重并发症，也是进行性骨化纤维发育不良（FOP）罕见疾病的标志。HO的发展是通过软骨内成骨的过程，包括炎症、软骨形成和成骨的阶段。从机制上讲，骨形态发生蛋白（BMP）信号传导参与了HO的发病机制。BMP通路也是铁稳态的重要调节因子，我们最近发现铁调节剂转铁蛋白受体2 （Tfr2）通过BMP-p38- mapk通路调节骨形成。基于我们发现Tfr2的胞外结构域（Tfr2- ecd）可以结合BMP配体，并可以作为配体陷阱来减少HO，我们假设Tfr2在HO的发展中起着至关重要的作用。因此，我们的目标是通过分析WT和Tfr2-/-小鼠HO的炎症期、软骨期和成骨期来确定Tfr2在HO各阶段的调控及其来源。此外，我们将确定铁和其他铁调节剂在小鼠HO中的作用。此外，我们的目的是验证Tfr2和其他铁调节因子在髋关节置换术后患者HO组织中的表达。为了揭示HO中Tfr2和BMP下游信号传导的潜在机制，我们将条件Tfr2缺陷小鼠以及BMP信号转导特异性条件小鼠置于HO中。此外，我们将在Tfr2-ECD中定义BMP结合位点，并测试较短的BMP结合Tfr2-ECD片段在体内阻断BMP-2诱导的骨化的能力。该项目将为铁调节剂对HO的影响提供新的见解。完善配体陷阱可能为消除HO和改善FOP提供一种新的治疗方法。

Heterotopic ossification (HO) is a process of ossification at abnormal anatomical sites. It is a common severe medical complication in patients after total hip replacement and it is a hallmark of the rare disease, fibrodysplasia ossificans progressiva (FOP). HO develops through a process of endochondral ossification involving stages of inflammation, chondrogenesis and osteogenesis. Mechanistically, bone morphogenetic protein (BMP) signaling has been implicated in the pathogenesis of HO. The BMP pathway is also an important regulator of iron homeostasis and we have recently shown that the iron regulator transferrin receptor 2 (Tfr2) regulates bone formation via the BMP-p38-MAPK pathway. Based on our discovery that the extracellular domain of Tfr2 (Tfr2-ECD) can bind BMP ligands and can be used as a ligand-trap to reduce HO, we hypothesize that Tfr2 plays a crucial role in the development of HO. Therefore, we aim to define the regulation of Tfr2 and its source in the various phases of HO by analyzing the inflammatory as well as the chondrogenic and osteogenic stages of HO in WT and Tfr2-/--mice. Furthermore we will determine the role of iron and other iron regulators in HO in mice. Additionally, we aim to validate the expression of Tfr2 and other iron regulators in HO tissue from patients after hip replacement surgeries. To unravel the underlying mechanisms of Tfr2 and BMP downstream signaling in HO, we will subject conditional Tfr2-deficient mice as well as conditional mice specific for BMP signal transducers to HO. Moreover, we will define the BMP binding sites within the Tfr2-ECD and test the ability of shorter BMP-binding Tfr2-ECD fragments to block BMP-2-induced ossification in vivo. The project will provide novel insights into the impact of iron regulators on HO. Refining the ligand trap may provide a novel therapeutic approach to abrogate HO and ameliorate FOP.