ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2016
Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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Who cites it
78 citing papers in PubMed, 122 citations in OpenAlex.
- BCX9250 is a potent small-molecule inhibitor of Activin A Receptor Type 1 (ACVR1/ALK2) for fibrodysplasia ossificans progressiva.JBMR plus · 2026Article
- Pathogenic transcriptional reprogramming of fibro-adipogenic progenitors in mice with FOP and its mitigation by inhibition of ACVR1 and activin A.bioRxiv : the preprint server for biology · 2026Article
- Single-Cell dissection of fibrodysplasia ossificans progressiva identifies SPP1 as a mediator of macrophage-fibroadipogenic progenitors crosstalk.Cellular and molecular life sciences : CMLS · 2026Article
- Exploring the potential application of roxadustat in chronic kidney disease-related osteoporosis based on the regulatory role of HIF-1α in bone metabolism.Histology and histopathology · 2026Review
- Treatment of heterotopic ossification via inhibiting the MMP-2/CDH5 axis through oral delivery of network pharmacology-predicted Chinese medicine.Materials today. Bio · 2026Article
- Primary Cilia Are Required for Efficient BMP Signaling in Traumatic Heterotopic Ossification.Biomedicines · 2026Article
- Angiogenesis in ossification of the posterior longitudinal ligament: progress from mechanism to targeted intervention.Frontiers in cell and developmental biology · 2026Review
- Medical guidelines for fibrodysplasia ossificans progressiva.JBMR plus · 2025Article
- Triptolide Attenuates Traumatic Heterotopic Ossification via Modulation of Inflammatory and Differentiation Pathways: Implications for Biochemical Toxicology.Journal of biochemical and molecular toxicology · 2025Article
- The efficiency of ozone therapy in the prevention of heterotopic bone formation in an animal model.Joint diseases and related surgery · 2025Article
- Advancements in mechanisms and drug treatments for fibrodysplasia ossificans progressiva.Journal of Zhejiang University. Science. B · 2025Review
- Interplay between ALK2Cell death discovery · 2025Article
- FOP: From Biomolecules to Hope.Biomolecules · 2025Article
- Molecular Developmental Biology of Fibrodysplasia Ossificans Progressiva: Measuring the Giant by Its Toe.Biomolecules · 2024Review
- The Role of Neuromodulation and Potential Mechanism in Regulating Heterotopic Ossification.Neurochemical research · 2024Review
- Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2024Article
- Cell Senescence in Heterotopic Ossification.Biomolecules · 2024Review
- Immunologic Aspects in Fibrodysplasia Ossificans Progressiva.Biomolecules · 2024Review
- Intersections of Fibrodysplasia Ossificans Progressiva and Traumatic Heterotopic Ossification.Biomolecules · 2024Review
- The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair.Bone research · 2024Article
18 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
Abstract
Hypoxia and inflammation are implicated in the episodic induction of heterotopic endochondral ossification (HEO); however, the molecular mechanisms are unknown. HIF-1α integrates the cellular response to both hypoxia and inflammation and is a prime candidate for regulating HEO. We investigated the role of hypoxia and HIF-1α in fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of HEO in humans. We found that HIF-1α increases the intensity and duration of canonical bone morphogenetic protein (BMP) signaling through Rabaptin 5 (RABEP1)-mediated retention of Activin A receptor, type I (ACVR1), a BMP receptor, in the endosomal compartment of hypoxic connective tissue progenitor cells from patients with FOP. We further show that early inflammatory FOP lesions in humans and in a mouse model are markedly hypoxic, and inhibition of HIF-1α by genetic or pharmacologic means restores canonical BMP signaling to normoxic levels in human FOP cells and profoundly reduces HEO in a constitutively active Acvr1(Q207D/+) mouse model of FOP. Thus, an inflammation and cellular oxygen-sensing mechanism that modulates intracellular retention of a mutant BMP receptor determines, in part, its pathologic activity in FOP. Our study provides critical insight into a previously unrecognized role of HIF-1α in the hypoxic amplification of BMP signaling and in the episodic induction of HEO in FOP and further identifies HIF-1α as a therapeutic target for FOP and perhaps nongenetic forms of HEO. © 2016 American Society for Bone and Mineral Research.
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