ArticleProceedings of the National Academy of Sciences of the United States of America2016
Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 141 papers.
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Who cites it
141 citing papers in PubMed, 220 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
- Tendon stem/progenitor cells in heterotopic ossification: functional regulation, molecular mechanisms and targeted therapeutic strategies.Journal of orthopaedic translation · 2026Review
- Identification of a Tenochondral Ossification Sequence Producing Heterotopic Ossification in Human Achilles Tendinopathy.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2026Article
- Heterotopic Ossification: Molecular Drivers, Subtype-Specific Mechanisms, and Translational Therapeutic Advances.Biomolecules · 2026Review
- Primary Cilia Are Required for Efficient BMP Signaling in Traumatic Heterotopic Ossification.Biomedicines · 2026Article
- Activation of PPARγ redirects fibro-adipogenic progenitors to replace ectopic bone with fat in models of fibrodysplasia ossificans progressiva and trauma-induced heterotopic ossification.bioRxiv : the preprint server for biology · 2026Article
- Thrombospondin 1 and 2 regulate mesenchymal progenitor cell fate and matrix organization.Bone research · 2026Article
- Integrin-mediated SPP1 signaling from macrophages orchestrates extracellular matrix remodeling and chondrogenesis in heterotopic ossification.Journal of translational medicine · 2025Article
- Triptolide Attenuates Traumatic Heterotopic Ossification via Modulation of Inflammatory and Differentiation Pathways: Implications for Biochemical Toxicology.Journal of biochemical and molecular toxicology · 2025Article
- Article
- FOP: From Biomolecules to Hope.Biomolecules · 2025Article
- Heterotopic ossification: Current developments and emerging potential therapies.Chinese medical journal · 2025Review
- Erroneous Differentiation of Tendon Stem/Progenitor Cells in the Pathogenesis of Tendinopathy: Current Evidence and Future Perspectives.Stem cell reviews and reports · 2025Review
- Polycystin-1 regulates tendon-derived mesenchymal stem cells fate and matrix organization in heterotopic ossification.Bone research · 2025Article
- A CD26Nature communications · 2025Article
- Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation.Bone research · 2025Article
- BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling.EMBO molecular medicine · 2025Article
- Fibroblasts in heterotopic ossification: mechanisms and therapeutic targets.International journal of biological sciences · 2025Review
- Sirtuin 3 reinforces acylcarnitine metabolism and maintains thermogenesis in brown adipose tissue of aging mice.Aging cell · 2024Article
81 more citing papers are in PubMed but not listed here.
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20 authors at 5 institutions in 1 country.
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Abstract
Pathologic extraskeletal bone formation, or heterotopic ossification (HO), occurs following mechanical trauma, burns, orthopedic operations, and in patients with hyperactivating mutations of the type I bone morphogenetic protein receptor ACVR1 (Activin type 1 receptor). Extraskeletal bone forms through an endochondral process with a cartilage intermediary prompting the hypothesis that hypoxic signaling present during cartilage formation drives HO development and that HO precursor cells derive from a mesenchymal lineage as defined by Paired related homeobox 1 (Prx). Here we demonstrate that Hypoxia inducible factor-1α (Hif1α), a key mediator of cellular adaptation to hypoxia, is highly expressed and active in three separate mouse models: trauma-induced, genetic, and a hybrid model of genetic and trauma-induced HO. In each of these models, Hif1α expression coincides with the expression of master transcription factor of cartilage, Sox9 [(sex determining region Y)-box 9]. Pharmacologic inhibition of Hif1α using PX-478 or rapamycin significantly decreased or inhibited extraskeletal bone formation. Importantly, de novo soft-tissue HO was eliminated or significantly diminished in treated mice. Lineage-tracing mice demonstrate that cells forming HO belong to the Prx lineage. Burn/tenotomy performed in lineage-specific Hif1α knockout mice (Prx-Cre/Hif1α(fl:fl)) resulted in substantially decreased HO, and again lack of de novo soft-tissue HO. Genetic loss of Hif1α in mesenchymal cells marked by Prx-cre prevents the formation of the mesenchymal condensations as shown by routine histology and immunostaining for Sox9 and PDGFRα. Pharmacologic inhibition of Hif1α had a similar effect on mesenchymal condensation development. Our findings indicate that Hif1α represents a promising target to prevent and treat pathologic extraskeletal bone.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.