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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 08, 2016
- Source ID
- 10.1002/stem.2515
Entities
People
- Ammar T. Qureshi
- Benjamin Lévi
- Bin Zhao
- Christopher Breuler
- David Cholok
- Ernestina Schipani
- Hsiao Hsin Sung
- John Li
- Joshua C Peterson
- Michael T. Chung
- Nobuhiro Kamiya
- R. Cameron Brownley
- Shailesh Agarwal
- Shawn J. Loder
- Shuli Li
- Thomas A. Davis
- Vesa Kaartinen
- Yuji Mishina
Organizations
- Albert Einstein College of Medicine
- American Association for the Surgery of Trauma
- Association for Academic Surgery
- Howard Hughes Medical Institute
- International FOP Association
- National Institutes of Health
- Naval Medical Research Center
- Tenri University
- University of Michigan
- University of Michigan School of Dentistry