The HIF-1α and mTOR Pathways Amplify Heterotopic Ossification
Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare congenital disorder caused by gain-of-function point mutations in the Activin receptor A type I (<i>ACVR1</i>, also known as <i>ALK2</i>) gene. FOP is characterized by episodic heterotopic ossification...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-01-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/14/2/147 |
| _version_ | 1797298737455824896 |
|---|---|
| author | Haitao Wang Frederick S. Kaplan Robert J. Pignolo |
| author_facet | Haitao Wang Frederick S. Kaplan Robert J. Pignolo |
| author_sort | Haitao Wang |
| collection | DOAJ |
| description | Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare congenital disorder caused by gain-of-function point mutations in the Activin receptor A type I (<i>ACVR1</i>, also known as <i>ALK2</i>) gene. FOP is characterized by episodic heterotopic ossification (HO) in skeletal muscles, tendons, ligaments, or other soft tissues that progressively causes irreversible loss of mobility. FOP mutations cause mild ligand-independent constitutive activation as well as ligand-dependent bone morphogenetic protein (BMP) pathway hypersensitivity of mutant ACVR1. BMP signaling is also a key pathway for mediating acquired HO. However, HO is a highly complex biological process involving multiple interacting signaling pathways. Among them, the hypoxia-inducible factor (HIF) and mechanistic target of rapamycin (mTOR) pathways are intimately involved in both genetic and acquired HO formation. HIF-1α inhibition or mTOR inhibition reduces HO formation in mouse models of FOP or acquired HO in part by de-amplifying the BMP pathway signaling. Here, we review the recent progress on the mechanisms of the HIF-1α and mTOR pathways in the amplification of HO lesions and discuss the future directions and strategies to translate the targeting of HIF-1α and the mTOR pathways into clinical interventions for FOP and other forms of HO. |
| first_indexed | 2024-03-07T22:40:18Z |
| format | Article |
| id | doaj.art-0ee5486526b04424ab942dfbac84108c |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-07T22:40:18Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-0ee5486526b04424ab942dfbac84108c2024-02-23T15:09:13ZengMDPI AGBiomolecules2218-273X2024-01-0114214710.3390/biom14020147The HIF-1α and mTOR Pathways Amplify Heterotopic OssificationHaitao Wang0Frederick S. Kaplan1Robert J. Pignolo2Department of Medicine, Geriatric Medicine & Gerontology, Mayo Clinic, Rochester, MN 55905, USADepartment of Orthopaedic Surgery, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Geriatric Medicine & Gerontology, Mayo Clinic, Rochester, MN 55905, USAFibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare congenital disorder caused by gain-of-function point mutations in the Activin receptor A type I (<i>ACVR1</i>, also known as <i>ALK2</i>) gene. FOP is characterized by episodic heterotopic ossification (HO) in skeletal muscles, tendons, ligaments, or other soft tissues that progressively causes irreversible loss of mobility. FOP mutations cause mild ligand-independent constitutive activation as well as ligand-dependent bone morphogenetic protein (BMP) pathway hypersensitivity of mutant ACVR1. BMP signaling is also a key pathway for mediating acquired HO. However, HO is a highly complex biological process involving multiple interacting signaling pathways. Among them, the hypoxia-inducible factor (HIF) and mechanistic target of rapamycin (mTOR) pathways are intimately involved in both genetic and acquired HO formation. HIF-1α inhibition or mTOR inhibition reduces HO formation in mouse models of FOP or acquired HO in part by de-amplifying the BMP pathway signaling. Here, we review the recent progress on the mechanisms of the HIF-1α and mTOR pathways in the amplification of HO lesions and discuss the future directions and strategies to translate the targeting of HIF-1α and the mTOR pathways into clinical interventions for FOP and other forms of HO.https://www.mdpi.com/2218-273X/14/2/147fibrodysplasia ossificans progressivahypoxia-inducible factormechanistic target of rapamycin (mTOR) pathwaysheterotopic ossification |
| spellingShingle | Haitao Wang Frederick S. Kaplan Robert J. Pignolo The HIF-1α and mTOR Pathways Amplify Heterotopic Ossification Biomolecules fibrodysplasia ossificans progressiva hypoxia-inducible factor mechanistic target of rapamycin (mTOR) pathways heterotopic ossification |
| title | The HIF-1α and mTOR Pathways Amplify Heterotopic Ossification |
| title_full | The HIF-1α and mTOR Pathways Amplify Heterotopic Ossification |
| title_fullStr | The HIF-1α and mTOR Pathways Amplify Heterotopic Ossification |
| title_full_unstemmed | The HIF-1α and mTOR Pathways Amplify Heterotopic Ossification |
| title_short | The HIF-1α and mTOR Pathways Amplify Heterotopic Ossification |
| title_sort | hif 1α and mtor pathways amplify heterotopic ossification |
| topic | fibrodysplasia ossificans progressiva hypoxia-inducible factor mechanistic target of rapamycin (mTOR) pathways heterotopic ossification |
| url | https://www.mdpi.com/2218-273X/14/2/147 |
| work_keys_str_mv | AT haitaowang thehif1aandmtorpathwaysamplifyheterotopicossification AT frederickskaplan thehif1aandmtorpathwaysamplifyheterotopicossification AT robertjpignolo thehif1aandmtorpathwaysamplifyheterotopicossification AT haitaowang hif1aandmtorpathwaysamplifyheterotopicossification AT frederickskaplan hif1aandmtorpathwaysamplifyheterotopicossification AT robertjpignolo hif1aandmtorpathwaysamplifyheterotopicossification |