Abstract
Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as all trans-retinoic acid, are produced in the cytoplasm and then interact with nuclear retinoic acid receptors (RARs) to up-regulate the transcription of target genes. The RARs can also interact with target gene response elements in the absence of retinoids and exert a transcriptional repression function. Studies from several labs, including ours, showed that chondrogenic cell differentiation and cartilage maturation require (i) the absence of retinoid signaling and (ii) the repression function by unliganded RARs. These and related insights led to the proposition that synthetic retinoid agonists could thus represent pharmacological agents to inhibit heterotopic ossification (HO), a process that recapitulates developmental skeletogenesis and involves chondrogenesis, cartilage maturation, and endochondral ossification. One form of HO is acquired and is caused by injury, and another severe and often fatal form of it is genetic and occurs in patients with fibrodysplasia ossificans progressiva (FOP). Mouse models of FOP bearing mutant ACVR1R206H, characteristic of most FOP patients, were used to test the ability of the retinoid agonists selective for RARα and RARγ against spontaneous and injury-induced HO. The RARγ agonists were found to be most effective, and one such compound, palovarotene, was selected for testing in FOP patients. The safety and effectiveness data from recent and ongoing phase II and phase III clinical trials support the notion that palovarotene may represent a disease-modifying treatment for patients with FOP. The post hoc analyses showed substantial efficacy but also revealed side effects and complications, including premature growth plate closure in some patients. Skeletally immature patients will need to be carefully weighed in any future regulatory indications of palovarotene as an important therapeutic option in FOP.
Highlights
The retinoids are metabolic derivatives of vitamin A, encompass a group of lipophilic molecules that include retinol, retinyl esters, and retinoic acid, and are essential for the embryonic development and postnatal functioning of multiple tissues and organs [1,2,3,4]
It is clear that retinoid signaling needs to be kept minimal or altogether prevented for skeletogenic cells to commit to chondrogenesis and produce cartilage templates undergoing endochondral ossification and bone formation
The translation of retinoid biology into clinically meaningful studies on safety and efficacy in fibrodysplasia ossificans progressiva (FOP) patients genetically predisposed to heterotopic ossification (HO) formation has occurred rapidly (Figure 2)
Summary
The retinoids are metabolic derivatives of vitamin A, encompass a group of lipophilic molecules that include retinol, retinyl esters, and retinoic acid, and are essential for the embryonic development and postnatal functioning of multiple tissues and organs [1,2,3,4]. This switch was accompanied by a steep decrease in the RALDH2 and CRABP expression and by a concurrent increase in CYP26 expression, (i) depleting the early chondrogenic progenitors of endogenous retinoids and carrier proteins, (ii) repressing the anti-chondrogenic pathways by unliganded RARs, and (iii) favoring the expression and activity of pro-chondrogenic pathways, including BMP signaling The latter mechanism was further explored in subsequent studies by comparing the global gene expression (over 360 genes) in limb bud progenitor cells under BMP stimulation toward chondrogenesis versus companion cells in which chondrogenesis was blocked by atRA [60]. It is the penetrant and effective anti-chondrogenic ability of atRA that has inspired and paved the way for the testing of synthetic retinoid agonists for the treatment of HO [29], as described below
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
