The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the RARA, RARB, RARG genes, respectively. As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements known as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation. Due to RAR/RXR heterodimers acting as subtrates to the non steroid hormone ligand retinoid they are extensively involved in cell differentiation, proliferation, and apoptosis.
Palovarotene is a RAR-γ Agonist for Fibrodysplasia Ossificans Progressiva Research
Palovarotene is a nuclear retinoic acid receptor γ (RAR-γ) agonist. In vivo, Palovarotene suppresses post-traumatic chondrogenesis and osteogenesis and mitigated trauma-induced ectopic bone formation. Palovarotene inhibits subcutaneous and intramuscular heterotopic ossification (HO) in mice. Palovarotene (1 mg/kg/day; 14 days; p.o.) starting on post-operative day (POD) 1 or POD-5. And HO amount, wound dehiscence and related processes are monitored for up to 84 days post injury. Palovarotene significantly decreases HO by 50 to 60% regardless of when the treatment started and if infection is present. Starting from day 1 of injury, Palovarotene treated half of the Acvr1cR206H/+ mice for 14 days. And the other half are received vehicle as control.
As a result, analysis by mCT and 3D image reconstruction at day 14 shows that large HO tissue masses have formed in the targeted leg of Acvr1cR206H/+ mutant mice receiving vehicle. But HO formation is greatly diminished in Palovarotene-treated companions by more than 80% based on bone volume/total volume quantification.
In conclusion, Palovarotene is a RAR-γ agonist for fibrodysplasia ossificans progressiva research.
Reference:
[2] J Bone Miner Res. 2016 Sep;31(9):1666-75.