Heterotopic ossification (HO) is the aberrant formation of mature, lamellar bone in nonosseous tissue. Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disorder that causes progressive HO in the ligaments, tendons, and muscles throughout the body. FOP is attributed to an autosomal mutation in activin receptor-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Initial studies show that mutant ALK2 drives HO by constitutively activating the BMP signaling pathway. Recently, mutant ALK2 has been shown to transduce Smad1/5 signaling and enhance chondrogenesis, calcification in response to Activin A, which normally signals through Smad2/3 and inhibits BMP signaling pathway. Furthermore, Activin A induces heterotopic bone formation via mutant ALK2, while inhibition of Activin A blocks spontaneous and trauma-induced HO. In this manuscript, we describe the molecular mechanism of the causative gene in FOP, mainly focusing on the prominent role of Activin A in HO. It reveals a potential strategy for prevention and treatment of FOP by inhibition of Activin A. Further studies are needed to explore the cellular and molecular mechanisms of Activin A in FOP in more detail.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680371 | PMC |
| http://dx.doi.org/10.1042/BSR20190377 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas.
Elife
October 2024
Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France.
Article Synopsis
- - Pediatric diffuse midline gliomas (pDMG) are aggressive childhood cancers characterized by fatal outcomes and linked to specific genetic mutations, particularly K27M in histone H3.
- - About 20 to 30% of these tumors have alterations in the BMP signaling pathway, specifically involving mutations in the BMP type I receptor ALK2, but the effects of BMP in non-mutated cases are not fully understood.
- - Recent research reveals that BMP2 and BMP7 are active in both wild-type and mutant tumors, and they work with the K27M mutation to alter cell behavior, indicating that the BMP pathway could be a target for treatment in pDMG.
Live-Cell Invasive Phenotyping Uncovers ALK2 as a Therapeutic Target in LKB1-Mutant Lung Cancer.
Cancer Res
November 2024
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.
Article Synopsis
- * Researchers developed an experimental system to screen for signaling pathways during early 3D invasion in lung adenocarcinoma, revealing that loss of LKB1 enhances BMP6 signaling, which influences iron regulation and tumor growth.
- * In pre-clinical models, targeting the ALK2/BMP6 signaling pathway showed significant anti-tumor effects, and elevated BMP6 levels were found in lung cancer patients with LKB1 mutations, suggesting a potential treatment approach for these patients.
Sex as a Critical Variable in Basic and Pre-Clinical Studies of Fibrodysplasia Ossificans Progressiva.
Biomolecules
February 2024
Department of Molecular & Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT 06269, USA.
Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino acid substitution in the type 1 bone morphogenetic protein (BMP) receptor ACVR1, a mutation that imparts responsiveness to activin A. Although it is well-established that biological sex is a critical variable in a range of physiological and disease processes, the impact of sex on HO in animal models of FOP has not been explored.
View Article and Find Full Text PDFThe HIF-1α and mTOR Pathways Amplify Heterotopic Ossification.
Biomolecules
January 2024
Department of Medicine, Geriatric Medicine & Gerontology, Mayo Clinic, Rochester, MN 55905, USA.
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 (, also known as ) 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.
View Article and Find Full Text PDFThe Activation of the Fibrodysplasia Ossificans Progressiva-Inducing ALK2-R206H Mutant Depends on the Distinct Homo-Oligomerization Patterns of ACVR2B and ACVR2A.
Cells
January 2024
Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.
Mutations in activin-like kinase 2 (ALK2), e.g., ALK2-R206H, induce aberrant signaling to SMAD1/5/8, leading to Fibrodysplasia Ossificans Progressiva (FOP).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!