Project Summary Heterotopic ossification (HO) is the pathologic formation of extra-skeletal bone forming almost exclusively at sites of mechanical stress, that occurs in ~20% of patients after hip arthroplasty, burns or musculoskeletal injury. Currently, no therapeutics or physical therapy-based protocols exist to prevent HO. In this regard, there is a void in our understanding of the causative mechanotransductive pathways behind this debilitating process. Our unbiased transcription profiles in mouse HO-mesenchymal progenitor cells (MPCs) recovered from HO sites in combination with immunostaining of mouse and human HO revealed that a series of mechanotranduction-linked pathways, including discoidin receptor 2 (DDR2), FAK and the Hippo effectors, YAP and TAZ, are highly upregulated in tandem with observed changes in extracellular matrix (ECM) alignment. Using a novel, regional MPC-specific inducible Cre system (Hoxa11-CreERT2), we have compiled preliminary data that support critical roles for DDR2 signaling and stage-specific immobilization in both triggering FAK/YAP/TAZ signaling and MPC lineage commitment, but also an unexpected function in controlling ECM alignment. Together, these observations have led to our central hypothesis that MPC DDR2 signaling is necessary for mobility-induced changes in ECM alignment that trigger aberrant osteochondral differentiation at HO sites and can be blocked by DDR2 inhibition or injury stage-specific immobilization. Aim 1: Define the role of DDR2 as a critical upstream regulator of FAK/YAP/TAZ signaling in controlling the induction and progression of HO. We hypothesize that DDR2-mechanotransductive signaling alters osteochondral differentiation and HO in vivo and can be targeted with cell specific deletion models or translatable clinical therapies. Aim 2: Determine the optimal post-injury timing during which MPCs can be redirected away from aberrant osteochondral fate and pathologic ECM alignment through immobilization-based intervention. We hypothesize that immobilization during the early proliferative phase after injury will block pathologic changes in ECM alignment with disease-ameliorating effects on MPC fate determination and aberrant ossification. Aim 3: Characterize the role of mobilization-induced DDR2 activation on collagen alignment/anisotropy and mechanotransductive signaling. We hypothesize that DDR2 activity drives ECM alignment independently of limb mobility in vivo or cyclic stretch in vitro. Impact: The proposed studies will provide a comprehensive and mechanistic understanding of how DDR2 and joint mobility regulate ECM alignment, cell fate and HO using conditional deletion models and clinical therapies.
|Effective start/end date||15/07/21 → 30/04/23|
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $428,360.00
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