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.
Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Sports Medicine, Tenri University, Japan.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Michigan, USA.Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA.Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA.Department of Orthopaedic Surgery, Orthopaedic Research Laboratories, University of Michigan, Michigan, USA.Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Michigan, USA.Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA. MeSH
Activin Receptors, Type IAnimalsBasic Helix-Loop-Helix Transcription FactorsCell LineageIntegrasesJointsMaleMesenchymal Stem CellsMice, Inbred C57BLMice, TransgenicMusclesOssification, HeterotopicPhenotypeTendonsWounds and Injuries
Pub Type(s)
Journal Article
