Heterotopic ossification (HO), the formation of ectopic endochondral bone in skeletal muscle and soft tissues, is a significant cause of morbidity from joint immobility and pain. The precise mechanisms responsible for HO are not known; however, its association with trauma, inflammation and biomechanical stress suggests a process of disordered injury repair and homeostasis. We have explored the underlying mechanisms of a monogenic cause of HO, fibrodysplasia ossificans progressiva (FOP), caused by activating mutations of the bone morphogenetic protein (BMP) type I receptor ALK2, whereas trauma-induced HO appears to be regulated by ALK2, ALK3 and potentially ALK6. FOP and acquired forms of HO share a common mechanism of inappropriate BMP signaling, but the manner by which BMP signals are interpreted to regulate ossification versus tissue regeneration remain incompletely understood. Significant gaps exist in how combinatorial BMP/TGFb signal transduction specifies diverse functions and cell fates in multipotent lineages. To address these mechanistic gaps, an innovative chemical biology platform has been devised using human- derived MSC that have been edited by CRISPR/Cas9 techniques, combined with a novel BMP/TGF-b pharmacologic probe identified from an active NCATS-TRND collaboration. This platform will permit the unequivocal mapping of individual ligand and receptor signaling, and the downstream impact on MSC plasticity in a non-overexpressed human cell system. This assay provides a platform for a high throughput screen to be performed with collaborators at NCATS-TRND to identify mechanistically novel modulators of ALK2, ALK3 and ALK6. Finally, insights and candidate molecules identified from these studies will be validated in a conditional knock-in mouse model of FOP, and in an authentic mouse model of trauma- and inflammation-induced HO. These studies will provide critical tools and insights into how the BMP signaling pathway contributes to pathologic tissue remodeling in musculoskeletal and degenerative disease, as well as in a broader set of conditions in which HO is associated with senescence, inflammation, and metabolic stress. New assay technologies, tool compounds, and translatable insights will be produced as a result of this work that will be relevant to many other disease-oriented fields of study.

Public Health Relevance

This proposal asks how bone morphogenetic protein signals, which normally regulate the activity of progenitor cells involved in the repair of muscle, blood vessels, connective tissues, and bone, may become dysregulated to cause disabling bone formation in muscle, tendons and ligaments in heterotopic ossification disease. In addition to providing insights and tools for understanding how bone morphogenetic proteins regulate this process, these studies may lead to more tolerable and effective therapies. The underlying mechanism of heterotopic ossification has relevance to a broader set of conditions in which inflammation and injury lead to abnormal ossification of diverse tissues in autoimmune, degenerative, and cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR057374-06A1
Application #
9596883
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Chen, Faye H
Project Start
2010-08-01
Project End
2023-06-30
Budget Start
2018-08-01
Budget End
2019-06-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
Alessi Wolken, Dana M; Idone, Vincent; Hatsell, Sarah J et al. (2018) The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva. Bone 109:210-217
Jiang, Jian-Kang; Huang, Xiuli; Shamim, Khalida et al. (2018) Discovery of 3-(4-sulfamoylnaphthyl)pyrazolo[1,5-a]pyrimidines as potent and selective ALK2 inhibitors. Bioorg Med Chem Lett 28:3356-3362
Dey, Devaveena; Wheatley, Benjamin M; Cholok, David et al. (2017) The traumatic bone: trauma-induced heterotopic ossification. Transl Res 186:95-111
Agarwal, Shailesh; Loder, Shawn J; Breuler, Christopher et al. (2017) Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification. Mol Ther 25:1974-1987
Dey, Devaveena; Bagarova, Jana; Hatsell, Sarah J et al. (2016) Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification. Sci Transl Med 8:366ra163
Nikolic, Ivana; Yu, Paul B (2016) The Role of Bone Marrow-derived Cells in Pulmonary Arterial Hypertension. What Lies Beneath? Am J Respir Crit Care Med 193:822-4
Morrell, Nicholas W; Bloch, Donald B; ten Dijke, Peter et al. (2016) Targeting BMP signalling in cardiovascular disease and anaemia. Nat Rev Cardiol 13:106-20
O'Rourke, Caitlin; Shelton, Georgia; Hutcheson, Joshua D et al. (2016) Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation. J Vis Exp :
Dey, Devaveena; Goldhamer, David J; Yu, Paul B (2015) Contributions of muscle-resident progenitor cells to homeostasis and disease. Curr Mol Biol Rep 1:175-188
Mayeur, Claire; Kolodziej, Starsha A; Wang, Amy et al. (2015) Oral administration of a bone morphogenetic protein type I receptor inhibitor prevents the development of anemia of inflammation. Haematologica 100:e68-71

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