title: Treatment of heterotopic ossification through remote ATP hydrolysis.
abstract: Heterotopic ossification (HO) is the pathologic development of ectopic bone in soft tissues because of a local or systemic inflammatory insult, such as burn injury or trauma. In HO, mesenchymal stem cells (MSCs) are inappropriately activated to undergo osteogenic differentiation. Through the correlation of in vitro assays and in vivo studies (dorsal scald burn with Achilles tenotomy), we have shown that burn injury enhances the osteogenic potential of MSCs and causes ectopic endochondral heterotopic bone formation and functional contractures through bone morphogenetic protein-mediated canonical SMAD signaling. We further demonstrated a prevention strategy for HO through adenosine triphosphate (ATP) hydrolysis at the burn site using apyrase. Burn site apyrase treatment decreased ATP, increased adenosine 3',5'-monophosphate, and decreased phosphorylation of SMAD1/5/8 in MSCs in vitro. This ATP hydrolysis also decreased HO formation and mitigated functional impairment in vivo. Similarly, selective inhibition of SMAD1/5/8 phosphorylation with LDN-193189 decreased HO formation and increased range of motion at the injury site in our burn model in vivo. Our results suggest that burn injury-exacerbated HO formation can be treated through therapeutics that target burn site ATP hydrolysis and modulation of SMAD1/5/8 phosphorylation.
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Peterson
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: De La Rosa
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Oluwatobi
authors.initials: O
authors.lastname: Eboda
authors.affiliation: Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring, MD 20910, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Cilwa
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Buchman
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Section of Plastic Surgery, Department of Biomedical Engineering, University of Michigan Health System, Ann Arbor, MI 48109, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Cederna
authors.affiliation: Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
authors.forename: Chuanwu
authors.initials: C
authors.lastname: Xi
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Morris
authors.affiliation: Department of Surgery, University of Texas Medical Branch at Galveston, and Shriners Hospitals for Children, Galveston, TX 77550, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
authors.affiliation: Department of Biologic and Material Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Krebsbach
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Stewart C
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. blevi@med.umich.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Levi
mesh_terms: D000125:Achilles Tendon / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology / Q000601:surgery; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001081:Apyrase / Q000494:pharmacology*; D002056:Burns / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D006868:Hydrolysis; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000201:enzymology; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009999:Ossification, Heterotopic / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D058971:Tenotomy / Q000009:adverse effects; D013997:Time Factors; D055815:Young Adult
chemical_list: D051896:Smad Proteins, Receptor-Regulated; D000255:Adenosine Triphosphate; D001081:Apyrase