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 postsurgical and posttraumatic contexts suggests a process of disordered injury repair. Further insights into the causes of HO may be gained from a congenital HO syndrome, fibrodysplasia ossificans progressiva (FOP). FOP is caused by """"""""constitutively-activating"""""""" mutations in the bone morphogenetic protein (BMP) type I receptor ALK2, which result in progressive and widespread joint ossifications triggered by minimal trauma or inflammation. Both FOP and acquired forms of HO lack effective therapies. In fact, there is significant evidence that both FOP and HO are caused by inappropriate activation of the BMP signaling pathway. It is not known how enhanced BMP signaling deviates the injury repair program, or which populations of cells mediate the effects of enhanced BMP signaling. To address these questions we have developed a mouse model of FOP in which a constitutively-active mutant form of ALK2 (caALK2) is inducibly expressed. Similar to affected humans, expression of this gene does not spontaneously induce HO, but vigorous ossification and joint fusion occur with additional stimuli of inflammation and muscle injury. Our subsequent studies with this model suggest that these caALK2 proteins may not be constitutively-active, as previously thought, but may sensitize cells to traditional ligand-mediated BMP signals.
In Aim 1 of this grant, we will employ this model to discern the mechanisms by which caALK2 sensitizes cells to BMP signals, testing whether caALK2 requires ligand-mediated signaling or functions independently. To identify the cellular progenitors which mediate the effects of enhanced BMP signaling, and which contribute to the ectopic bone lesions, in Aim 2 we have targeted the expression of mutant caALK2 to several candidate progenitor lineages. Using a complement of cell-based, genetic targeting, and adoptive transfer techniques, we will systematically determine the impact of expressing caALK2 in compartments with known osteogenic potential, including skeletal muscle satellite cells, vascular pericytes, as well as bone-marrow derived lineages.
In Aim 3, we examine the role of innate immune signaling in the development of ectopic bone in this model. Understanding how caALK2 mutations alter the consequences of BMP signaling could highlight novel molecular or cellular targets for management of HO. This proposal seeks to elucidate how enhanced BMP signaling impacts mesenchymal progenitors and governs adaptive and maladaptive osteogenesis at the interface of injury, inflammation, and regeneration.
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 inappropriate bone formation in the human diseases of heterotopic ossification and fibrodysplasia ossificans progressiva. In addition to providing insights into the mechanism of these poorly understood processes, these studies may identify much needed novel approaches for their management. These mechanisms have relevance to a broader set of conditions in which inflammation and injury appear to lead to abnormal ossification in autoimmune, cardiac, and vascular disease.
|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 :|
|Chun, Hyung J; Yu, Paul B (2015) Elafin in pulmonary arterial hypertension. Beyond targeting elastases. Am J Respir Crit Care Med 191:1217-9|
|Hatsell, Sarah J; Idone, Vincent; Wolken, Dana M Alessi et al. (2015) ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7:303ra137|
Showing the most recent 10 out of 31 publications