Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

摘要: Pathologic extraskeletal bone formation, or heterotopic ossification (HO), occurs following mechanical trauma, burns, orthopedic operations, and in patients with hyperactivating mutations of the type I morphogenetic protein receptor ACVR1 (Activin 1 receptor). Extraskeletal forms through an endochondral process a cartilage intermediary prompting hypothesis that hypoxic signaling present during formation drives HO development precursor cells derive from mesenchymal lineage as defined by Paired related homeobox (Prx). Here we demonstrate Hypoxia inducible factor-1α (Hif1α), key mediator cellular adaptation to hypoxia, is highly expressed active three separate mouse models: trauma-induced, genetic, hybrid model genetic trauma-induced HO. In each these models, Hif1α expression coincides master transcription factor cartilage, Sox9 [(sex determining region Y)-box 9]. Pharmacologic inhibition using PX-478 rapamycin significantly decreased inhibited formation. Importantly, de novo soft-tissue was eliminated diminished treated mice. Lineage-tracing mice forming belong Prx lineage. Burn/tenotomy performed lineage-specific knockout (Prx-Cre/Hif1α(fl:fl)) resulted substantially HO, again lack Genetic loss marked Prx-cre prevents condensations shown routine histology immunostaining for PDGFRα. had similar effect on condensation development. Our findings indicate represents promising target prevent treat pathologic bone.