@article{3cacd58d1a05470781e50cd6c186bfbf,
title = "Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon",
abstract = "The pathologic development of heterotopic ossification (HO) is well described in patients with extensive trauma or with hyperactivating mutations of the bone morphogenetic protein (BMP) receptor ACVR1. However, identification of progenitor cells contributing to this process remains elusive. Here we show that connective tissue cells contribute to a substantial amount of HO anlagen caused by trauma using postnatal, tamoxifen-inducible, scleraxis-lineage restricted reporter mice (Scx-creERT2/tdTomatofl/fl). When the scleraxis-lineage is restricted specifically to adults prior to injury marked cells contribute to each stage of the developing HO anlagen and coexpress markers of endochondral ossification (Osterix, SOX9). Furthermore, these adult preinjury restricted cells coexpressed mesenchymal stem cell markers including PDGFRα, Sca1, and S100A4 in HO. When constitutively active ACVR1 (caACVR1) was expressed in scx-cre cells in the absence of injury (Scx-cre/caACVR1fl/fl), tendons and joints formed HO. Postnatal lineage-restricted, tamoxifen-inducible caACVR1 expression (Scx-creERT2/caACVR1fl/fl) was sufficient to form HO after directed cardiotoxin-induced muscle injury. These findings suggest that cells expressing scleraxis within muscle or tendon contribute to HO in the setting of both trauma or hyperactive BMP receptor (e.g., caACVR1) activity. Stem Cells 2017;35:705–710.",
keywords = "Adult stem cells, Bone, Fibrodysplasia ossificans progressiva, Heterotopic ossification, Osteoblast, Progenitor cells, Skeleton, Tissue specific stem cells",
author = "Shailesh Agarwal and Loder, {Shawn J.} and David Cholok and Joshua Peterson and John Li and Christopher Breuler and {Cameron Brownley}, R. and {Hsin Sung}, Hsiao and Chung, {Michael T.} and Nobuhiro Kamiya and Shuli Li and Bin Zhao and Vesa Kaartinen and Davis, {Thomas A.} and Qureshi, {Ammar T.} and Ernestina Schipani and Yuji Mishina and Benjamin Levi",
note = "Funding Information: We thank Dr. Ron Schweitzer for developing the Scx-Cre mice used in this manuscript as well as Dr. Schweitzer and Dr. Zelzer's input on our data. We also thank Chris Mendias and Kris Sugg for their input. Some of this work was supported by Congressional Directed Medical Research Programs grant (CDMRP: W81XWH-14-2-0010). Some of the authors (A.T.Q., J.A.F., T.A.D.) are employees of the US Government. This work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. §101 defined a US Government work as a work prepared by a military service member or employees of the U.S. Government as part of that person's official duties. The opinions or assertions contained in this article are the private views of the authors and are not to be construed as reflecting the views, policy or positions of the Department of the Navy, Department of Defense nor the U.S. Government. Some of the study described here was conducted under protocol (12-OUMD-20s), reviewed and approved by the Walter Reed Army Institute of Research/Naval Medical Research Center Institutional Animal Care and Use Committee in compliance with all applicable Federal regulations governing the protection of animals in research. B.L. received funding from NIH/NIGMS -K08GM109105-0, the Association for Academic Surgery Roslyn Award and the Research & Education Foundation Scholarship, American Association for the Surgery of Trauma Research & Education Foundation Scholarship, Plastic Surgery Foundation/AAPS Pilot Award, International FOP Association and American Association of Plastic Surgery Research Fellowship. S.L is supported by the Howard Hughes Medical Institute Medical Research Fellowship. Y.M. received funding from NIH/NIDCR – R01DE020843 and DOD: W81XWH1120073-DMRDP. SA: Supported by the Coller Society Research Fellowship, NIH Loan Repayment Program, NIH, F32AR06649901A1 and Plastic Surgery Foundation. Publisher Copyright: {\textcopyright} 2016 AlphaMed Press",
year = "2017",
month = mar,
day = "1",
doi = "10.1002/stem.2515",
language = "English (US)",
volume = "35",
pages = "705--710",
journal = "STEM CELLS",
issn = "1066-5099",
publisher = "AlphaMed Press",
number = "3",
}