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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.PN

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.

Authors+Show Affiliations

Department of Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Orthopedic Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Surgery, University of Michigan, Ann Arbor, MI 48109;Department of Surgery, Massachusetts General Hospital, Boston, MA 02114;Department of Surgery, Shriners Hospital for Children and University of Texas Medical Branch, Galveston, TX 77555;Department of Surgery, Genome Technology Center, Stanford University, Palo Alto, CA 94305;Department of Developmental Biology, Harvard Dental School, Boston, MA 02115;Department of Developmental Biology, Harvard Dental School, Boston, MA 02115;Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD 20910;Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109.Department of Orthopedic Surgery, University of Michigan, Ann Arbor, MI 48109; eschipan@med.umich.edu blevi@umich.edu.Department of Surgery, University of Michigan, Ann Arbor, MI 48109; eschipan@med.umich.edu blevi@umich.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

26721400

Citation

Agarwal, Shailesh, et al. "Inhibition of Hif1α Prevents Both Trauma-induced and Genetic Heterotopic Ossification." Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 3, 2016, pp. E338-47.
Agarwal S, Loder S, Brownley C, et al. Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification. Proc Natl Acad Sci U S A. 2016;113(3):E338-47.
Agarwal, S., Loder, S., Brownley, C., Cholok, D., Mangiavini, L., Li, J., Breuler, C., Sung, H. H., Li, S., Ranganathan, K., Peterson, J., Tompkins, R., Herndon, D., Xiao, W., Jumlongras, D., Olsen, B. R., Davis, T. A., Mishina, Y., Schipani, E., & Levi, B. (2016). Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification. Proceedings of the National Academy of Sciences of the United States of America, 113(3), E338-47. https://doi.org/10.1073/pnas.1515397113
Agarwal S, et al. 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. PubMed PMID: 26721400.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification. AU - Agarwal,Shailesh, AU - Loder,Shawn, AU - Brownley,Cameron, AU - Cholok,David, AU - Mangiavini,Laura, AU - Li,John, AU - Breuler,Christopher, AU - Sung,Hsiao H, AU - Li,Shuli, AU - Ranganathan,Kavitha, AU - Peterson,Joshua, AU - Tompkins,Ronald, AU - Herndon,David, AU - Xiao,Wenzhong, AU - Jumlongras,Dolrudee, AU - Olsen,Bjorn R, AU - Davis,Thomas A, AU - Mishina,Yuji, AU - Schipani,Ernestina, AU - Levi,Benjamin, Y1 - 2015/12/31/ PY - 2016/1/2/entrez PY - 2016/1/2/pubmed PY - 2016/6/14/medline KW - HIF1α KW - Prx KW - cartilage KW - heterotopic ossification KW - mesenchymal condensation SP - E338 EP - 47 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 113 IS - 3 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/26721400/Inhibition_of_Hif1α_prevents_both_trauma_induced_and_genetic_heterotopic_ossification_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=26721400 DB - PRIME DP - Unbound Medicine ER -