ECTS2016 Poster Presentations Other diseases of bone and mineral metabolism (52 abstracts)
Tracking inflammation in mouse model of fibrodysplasia ossificans progressiva prior to the detection of heterotopic ossification as a potential biomarker
Kalyan Nannuru , Johanna Jimenez , Lily Huang , Xialing Wen , Lili Wang , LiQin Xie , Vincent Idone , Andrew Murphy , Sarah Hatsell & Aris Economides
Regeneron Pharmaceuticals Inc, Tarrytown, New York, USA.
Fibrodysplasia ossificans progressiva (FOP) is a rare debilitating genetic disease characterized by abnormal progressive heterotopic endochondrial ossification of soft tissues. FOP results from mutations in the intracellular domain of the type I BMP receptor ACVR1 (ALK2) the most common of which is R206H. FOP mutations alter the sensitivity of ACVR1 to Activin A from an antagonist to an agonist. We have previously shown that Activin A is necessary and sufficient for driving heterotopic ossification HO in our mouse model of FOP (Acvr1[R206H]FlEx/+; Rosa-CreERT2 mice). HO in FOP patients is often preceded by a flare-up, which might be due to a soft tissue injury or other inflammatory stimuli. Hence detection of inflammation in FOP patients may offer a potential therapeutic window for intervention before HO formation. In Acvr1[R206H]FlEx/+; Rosa-CreERT2 mice we visualized the homing of macrophages or phagocytes to the site of injury in response to cardiotoxin-induced muscle injury within 24 h. Subsequently, we observed heterotopic bone formation at the site of injury by day 10. Macrophages and phagocytes that respond to inflammatory stimuli were tracked in vivo using inflammation probes that target activated phagocytes with chemiluminescence. Macrophages were also tracked by intravenous administration of radio dense Exitron nano particles, which were taken up by the macrophages enabling monitoring by in vivo μCT imaging. Our findings demonstrate that HO formation is preceded by an inflammatory response at the site of cardiotoxin-induced injury. Macrophages and phagocyte that home to the site of injury might be responsible for initiating heterotopic ossification by secreting agents such as Activin A that drive endochondrial ossification. Further imaging studies using specific and sensitive inflammatory probes aimed at detecting inflammation at the earliest possible time before progressive HO sets in will be valuable in development of new therapeutic interventions.
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Bone Abstracts
ISSN 2052-1219 (online)
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