Retinoid Agonists in the Targeting of Heterotopic Ossification

Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as <i>all trans</i>-retinoic acid, are produced in the cytoplasm and then interact with nuclear retinoic acid receptors (RARs) to...

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Autores principales:	Robert J. Pignolo, Maurizio Pacifici
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	retinoids retinoic acid receptors chondrogenesis heterotopic ossification palovarotene Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d9071ccc6f0448b5b8c5c7d07001504b
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spelling	oai:doaj.org-article:d9071ccc6f0448b5b8c5c7d07001504b2021-11-25T17:13:14ZRetinoid Agonists in the Targeting of Heterotopic Ossification10.3390/cells101132452073-4409https://doaj.org/article/d9071ccc6f0448b5b8c5c7d07001504b2021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3245https://doaj.org/toc/2073-4409Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as <i>all trans</i>-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.Robert J. PignoloMaurizio PacificiMDPI AGarticleretinoidsretinoic acid receptorschondrogenesisheterotopic ossificationpalovaroteneBiology (General)QH301-705.5ENCells, Vol 10, Iss 3245, p 3245 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	retinoids retinoic acid receptors chondrogenesis heterotopic ossification palovarotene Biology (General) QH301-705.5
spellingShingle	retinoids retinoic acid receptors chondrogenesis heterotopic ossification palovarotene Biology (General) QH301-705.5 Robert J. Pignolo Maurizio Pacifici Retinoid Agonists in the Targeting of Heterotopic Ossification
description	Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as <i>all trans</i>-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.
format	article
author	Robert J. Pignolo Maurizio Pacifici
author_facet	Robert J. Pignolo Maurizio Pacifici
author_sort	Robert J. Pignolo
title	Retinoid Agonists in the Targeting of Heterotopic Ossification
title_short	Retinoid Agonists in the Targeting of Heterotopic Ossification
title_full	Retinoid Agonists in the Targeting of Heterotopic Ossification
title_fullStr	Retinoid Agonists in the Targeting of Heterotopic Ossification
title_full_unstemmed	Retinoid Agonists in the Targeting of Heterotopic Ossification
title_sort	retinoid agonists in the targeting of heterotopic ossification
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d9071ccc6f0448b5b8c5c7d07001504b
work_keys_str_mv	AT robertjpignolo retinoidagonistsinthetargetingofheterotopicossification AT mauriziopacifici retinoidagonistsinthetargetingofheterotopicossification
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Retinoid Agonists in the Targeting of Heterotopic Ossification

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