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.
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