Heterotopic ossification (HO) consists of ectopic cartilage and bone formation 
following severe trauma or invasive surgeries, and a genetic form of it 
characterizes patients with Fibrodysplasia Ossificans Progressiva (FOP). Recent 
mouse studies showed that HO was significantly inhibited by systemic treatment 
with a corticosteroid or the retinoic acid receptor γ agonist Palovarotene. 
Because these drugs act differently, the data raised intriguing questions 
including whether the drugs affected HO via similar means, whether a combination 
therapy would be more effective or whether the drugs may hamper each other's 
action. To tackle these questions, we used an effective HO mouse model involving 
subcutaneous implantation of Matrigel plus rhBMP2, and compared the 
effectiveness of prednisone, dexamathaosone, Palovarotene or combination of. 
Each corticosteroid and Palovarotene reduced bone formation at max doses, and a 
combination therapy elicited similar outcomes without obvious interference. 
While Palovarotene had effectively prevented the initial cartilaginous phase of 
HO, the steroids appeared to act more on the bony phase. In reporter assays, 
dexamethasone and Palovarotene induced transcriptional activity of their 
respective GRE or RARE constructs and did not interfere with each other's 
pathway. Interestingly, both drugs inhibited the activity of a reporter 
construct for the inflammatory mediator NF-κB, particularly in combination. In 
good agreement, immunohistochemical analyses showed that both drugs markedly 
reduced the number of mast cells and macrophages near and within the ectopic 
Matrigel mass and reduced also the number of progenitor cells. In sum, 
corticosteroids and Palovarotene appear to block HO via common and distinct 
mechanisms. Most importantly, they directly or indirectly inhibit the 
recruitment of immune and inflammatory cells present at the affected site, thus 
alleviating the effects of key HO instigators.