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.
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Loder
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cholok
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Peterson
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: John
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Breuler
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: R
authors.initials: R
authors.lastname: Cameron Brownley
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: Hsiao
authors.initials: H
authors.lastname: Hsin Sung
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Chung
authors.affiliation: Department of Sports Medicine, Tenri University, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kamiya
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: Shuli
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Michigan, USA.
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Davis
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA.
authors.forename: Ammar T
authors.initials: AT
authors.lastname: Qureshi
authors.affiliation: Department of Orthopaedic Surgery, Orthopaedic Research Laboratories, University of Michigan, Michigan, USA.
authors.forename: Ernestina
authors.initials: E
authors.lastname: Schipani
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Michigan, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Levi
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019070:Cell Lineage; D019426:Integrases / Q000378:metabolism; D007596:Joints / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009132:Muscles / Q000473:pathology*; D009999:Ossification, Heterotopic / Q000209:etiology / Q000473:pathology*; D010641:Phenotype; D013710:Tendons / Q000473:pathology*; D014947:Wounds and Injuries / Q000150:complications / Q000473:pathology
chemical_list: D030201:Activin Receptors, Type I; D051792:Basic Helix-Loop-Helix Proteins; D019426:Integrases; C503815:Scx protein, mouse; C498943:Acvr1 protein, mouse; C045073:Cre recombinase
keywords: Adult stem cells; Bone; Fibrodysplasia ossificans progressiva; Heterotopic ossification; Osteoblast; Progenitor cells; Skeleton; Tissue specific stem cells