2. Academic Validation
  3. Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

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

  • Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):E338-47. doi: 10.1073/pnas.1515397113.
Shailesh Agarwal 1,  Shawn Loder 1,  Cameron Brownley 1,  David Cholok 1,  Laura Mangiavini 2,  John Li 1,  Christopher Breuler 1,  Hsiao H Sung 1,  Shuli Li 1,  Kavitha Ranganathan 1,  Joshua Peterson 1,  Ronald Tompkins 3,  David Herndon 4,  Wenzhong Xiao 5,  Dolrudee Jumlongras 6,  Bjorn R Olsen 6,  Thomas A Davis 7,  Yuji Mishina 8,  Ernestina Schipani 9,  Benjamin Levi 10
Affiliations

Affiliations

  • 1 Department of Surgery, University of Michigan, Ann Arbor, MI 48109;
  • 2 Department of Orthopedic Surgery, University of Michigan, Ann Arbor, MI 48109;
  • 3 Department of Surgery, Massachusetts General Hospital, Boston, MA 02114;
  • 4 Department of Surgery, Shriners Hospital for Children and University of Texas Medical Branch, Galveston, TX 77555;
  • 5 Department of Surgery, Genome Technology Center, Stanford University, Palo Alto, CA 94305;
  • 6 Department of Developmental Biology, Harvard Dental School, Boston, MA 02115;
  • 7 Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD 20910;
  • 8 Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109.
  • 9 Department of Orthopedic Surgery, University of Michigan, Ann Arbor, MI 48109; eschipan@med.umich.edu blevi@umich.edu.
  • 10 Department of Surgery, University of Michigan, Ann Arbor, MI 48109; eschipan@med.umich.edu blevi@umich.edu.
PMID: 26721400 DOI: 10.1073/pnas.1515397113
Abstract

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

Keywords

HIF1α; Prx; cartilage; heterotopic ossification; mesenchymal condensation.

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