HIF1α gates tendon response to overload and drives tendinopathy independently of vascular recruitment

Tendons are sparsely vascularized connective tissues that link muscles to bones, withstanding some of the highest mechanical stresses in the body. Mechanical overloading and tissue hypervascularity are implicated in tendinopathy, a common musculoskeletal disorder, yet their mechanistic roles remain unclear. Here, we identify hypoxia-inducible factor 1α (HIF1α) as not only a marker but also a driver of tendinopathy. Histological and multiomics evaluation of human tendinopathic samples revealed extensive extracellular matrix remodeling, including pathological collagen cross-linking coinciding with active hypoxic signaling. Hypothesizing a causal contribution of hypoxia signaling, we generated mice with tenocyte-targeted deletions of the von Hippel-Lindau (<i>Vhl</i>) gene, which controls hypoxia signaling by regulating HIFα degradation. <i>Vhl</i> inactivation was sufficient to induce pathological hallmarks of tendinopathy, such as collagen matrix disorganization, cross-linking, altered mechanics, and neurovascular ingrowth. This phenotype was HIF1α dependent given that codeleting HIF1α rescued tendon morphology and mechanics. Moreover, deleting vascular endothelial growth factor A (<i>Vegfa</i>) alongside VHL effectively suppressed neovascularization but failed to rescue extracellular matrix abnormalities or restore mechanical function, emphasizing a direct role of HIF1α in driving tendon disease independently of angiogenesis. Mechanistically, we found that HIF1α activation was strain dependent in primary cultured human tendon cells and induced by mechanical overload in murine tendon explants. Furthermore, genetically removing <i>Hif1</i>α from tenocytes prevented aberrant tendon remodeling in response to chronic overload. These findings position HIF1α signaling as a central driver of tendinopathy that acts through a maladaptive tissue response to chronic overload, providing mechanistic insights that could be leveraged for therapeutic approaches.

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Publication Details

Journal
Science Translational Medicine
Published
2026-01-07
DOI
https://doi.org/10.1126/scitranslmed.adt1228
Citations
1
Primary Topic
Tendon Structure and Treatment
Type
article
Field-Weighted Citation Impact
39.58
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article

HIF1α gates tendon response to overload and drives tendinopathy independently of vascular recruitment

Dirk Elewaut, Guillermo Turiel, Sarah Morice, Farah Selman et al.
1 citations
Science Translational Medicine
Tendon Structure and Treatment
39.58
article

HIF1α gates tendon response to overload and drives tendinopathy independently of vascular recruitment

Dirk Elewaut, Guillermo Turiel, Sarah Morice, Farah Selman, Nathalie Tisch, Katrien De Bock, Helma Wennemers, Barbara Niederoest, Karl Wieser, Matthew R. Aronoff, Evi Masschelein, Raphaela Ardicoglu, Jess G. Snedeker, Stefania L. Wunderli, U Blache, Fabian S. Passini, Lieke Mous, Shauni Loopmans, Florence Marti, Diane E. Taylor, Izabella Niewczas, Didier Surdez, Amro A. Hussien, Bart Ghesquière, Maja Wolleb, Maja Bollhalder, Monika Hilbe, G. Moschini, Jonathan Clark, Santiago Ardiles, Archana G. Mohanan, Olivia Baumberger, Sandro F. Fucentese, Patrick K. Jaeger
article en
1 citations

Abstract

Tendons are sparsely vascularized connective tissues that link muscles to bones, withstanding some of the highest mechanical stresses in the body. Mechanical overloading and tissue hypervascularity are implicated in tendinopathy, a common musculoskeletal disorder, yet their mechanistic roles remain unclear. Here, we identify hypoxia-inducible factor 1α (HIF1α) as not only a marker but also a driver of tendinopathy. Histological and multiomics evaluation of human tendinopathic samples revealed extensive extracellular matrix remodeling, including pathological collagen cross-linking coinciding with active hypoxic signaling. Hypothesizing a causal contribution of hypoxia signaling, we generated mice with tenocyte-targeted deletions of the von Hippel-Lindau (<i>Vhl</i>) gene, which controls hypoxia signaling by regulating HIFα degradation. <i>Vhl</i> inactivation was sufficient to induce pathological hallmarks of tendinopathy, such as collagen matrix disorganization, cross-linking, altered mechanics, and neurovascular ingrowth. This phenotype was HIF1α dependent given that codeleting HIF1α rescued tendon morphology and mechanics. Moreover, deleting vascular endothelial growth factor A (<i>Vegfa</i>) alongside VHL effectively suppressed neovascularization but failed to rescue extracellular matrix abnormalities or restore mechanical function, emphasizing a direct role of HIF1α in driving tendon disease independently of angiogenesis. Mechanistically, we found that HIF1α activation was strain dependent in primary cultured human tendon cells and induced by mechanical overload in murine tendon explants. Furthermore, genetically removing <i>Hif1</i>α from tenocytes prevented aberrant tendon remodeling in response to chronic overload. These findings position HIF1α signaling as a central driver of tendinopathy that acts through a maladaptive tissue response to chronic overload, providing mechanistic insights that could be leveraged for therapeutic approaches.

Science Translational MedicineVol. 18(831)
Babraham Institute (GB), University of New Mexico (US), University of Zurich (CH), Ghent University (BE), ETH Zurich (CH), Institute for Biomedical Engineering (CH), VIB-KU Leuven Center for Cancer Biology (BE), University Hospital of Zurich (CH), Universitätsklinik Balgrist (CH), VIB-UGent Center for Inflammation Research (BE), Fraunhofer Institute for Cell Therapy and Immunology (DE), Max Planck Institute for Molecular Biomedicine (DE), Weizmann Institute of Science (IL), KU Leuven (BE)
Openalex Percentile: Top 2%
Tendon Structure and Treatment
39.58
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