title: Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification.
abstract: Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1R206Hknock-in allele recapitulate the phenotypic spectrum of FOP, including injury-responsive intramuscular HO and spontaneous articular, tendon, and ligament ossification. The cells that drive HO in these diverse tissues can be compartmentalized into two lineages: an Scx+tendon-derived progenitor that mediates endochondral HO of ligaments and joints without exogenous injury, and a muscle-resident interstitial Mx1+population that mediates intramuscular, injury-dependent endochondral HO. Expression of Acvr1R206Hin either lineage confers aberrant gain of BMP signaling and chondrogenic differentiation in response to activin A and gives rise to mutation-expressing hypertrophic chondrocytes in HO lesions. Compared to Acvr1R206H, expression of the man-made, ligand-independent ACVR1Q207Dmutation accelerates and increases the penetrance of all observed phenotypes, but does not abrogate the need for antecedent injury in muscle HO, demonstrating the need for an injury factor in addition to enhanced BMP signaling. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr1R206Hknock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. Thus, diverse phenotypes of HO found in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in nonoverlapping tissue-resident progenitor pools that may be addressed by systemic therapy or by modulating injury-mediated factors involved in their local recruitment.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Devaveena
authors.initials: D
authors.lastname: Dey
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Bagarova
authors.affiliation: Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Hatsell
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Kelli A
authors.initials: KA
authors.lastname: Armstrong
authors.affiliation: Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joerg
authors.initials: J
authors.lastname: Ermann
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Vonner
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Agustin H
authors.initials: AH
authors.lastname: Mohedas
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Lee
authors.affiliation: Departments of Internal Medicine, Endocrine Section, and Epidemiology and Biostatistics, VU University Medical Center, PO Box 7057, Amsterdam 1007 MB, Netherlands.
authors.forename: Elisabeth M W
authors.initials: EM
authors.lastname: Eekhoff
authors.affiliation: Departments of Internal Medicine, Endocrine Section, and Epidemiology and Biostatistics, VU University Medical Center, PO Box 7057, Amsterdam 1007 MB, Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: van Schie
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Marie B
authors.initials: MB
authors.lastname: Demay
authors.affiliation: Children's Cancer Therapy Development Institute, 12655 SW Beaverdam Road-West, Beaverton, OR 97005, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA.|Joslin Diabetes Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.|Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. pbyu@partners.org.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics; D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D019070:Cell Lineage; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D005838:Genotype; D006801:Humans; D007596:Joints / Q000378:metabolism; D008022:Ligaments / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D064547:Myxovirus Resistance Proteins / Q000378:metabolism*; D009999:Ossification, Heterotopic / Q000378:metabolism*; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology*
chemical_list: D030201:Activin Receptors, Type I; D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D008024:Ligands; D064547:Myxovirus Resistance Proteins; C579071:MX1 protein, human; C579070:Mx1 protein, mouse; C093504:SCX protein, human; C503815:Scx protein, mouse; C498943:Acvr1 protein, mouse