Targeting jmjd3 mitigates heterotopic ossification

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

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.