The developing tendon and enthesis are hypoxic and rely on hypoxia-inducible factor 1a ( Hif1a ) during postnatal development
Year: 2025
Type: preprint
Abstract: The tendon-bone enthesis is a specialized fibrocartilaginous tissue crucial for muscle-to-bone force transmission, yet its postnatal development is not fully understood. Emerging evidence suggests hypoxia plays a pivotal role in enthesis maturation akin to its function in skeletal growth plates, with Hypoxia Inducible Factor 1 alpha (HIF-1α) acting as a key regulator of cellular adaptation (e.g., cell survival, extracellular matrix (ECM) deposition). Here, we investigated the spatial and temporal dynamics of hypoxia in the murine Achilles tendon enthesis and elucidated the role of Hif1a in enthesis cell survival and ECM formation using Scleraxis-lineage conditional knockout (ScxCre; Hif1a cKO) mice. We found that while neonatal tendons rapidly resolve hypoxia after birth, the enthesis maintains a hypoxic niche through postnatal day 5, mirroring a gradient observed in growth plates. Disruption of HIF-1α in enthesis-resident cells resulted in pronounced deficits in grip strength, abnormal tendon-bone attachment morphology, disrupted calcaneal architecture, impaired mineralization, and significant ECM disorganization. Histological analyses revealed persistent cell death and loss of the characteristic fibrocartilaginous gradient in cKO entheses, including dysregulated collagen alignment. In vitro, HIF-1α-deficient tendon fibroblasts exhibited blunted transcriptional responses to hypoxia, altered metabolic gene expression, and changes in ECM deposition. Collectively, our findings illuminate hypoxia as a sustained niche in the postnatal enthesis, with HIF-1α critically required for cell survival, ECM organization, and enthesis structural integrity. This work advances our understanding of enthesis biology and provides insights relevant to tendon-bone attachment disorders and regenerative strategies.
Authors: Stephanie S. Steltzer, Nicole Migotsky, Tessa Phillips, Syeda N. Lamia, Ki Won Lee, Sueng-Ho Bae, Connor Leek, Sydney Grossman, Moaid Shaik, Allison Risha, Kaitlyn Frey, Claudia Loebel, Jun Hee Lee, Yatrik M. Shah, Adam C. Abraham, Megan L. Killian
Language: English
Subfield: Orthopedics and Sports Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G105385035, G1226414983, G4030466733, G4599319085, G4880957766, CAREER: Remodeling and Damage of the Tendon Attachment During Postnatal Growth, G7500650239, New 3D and 4D Image-Based Clinical Measures of Atrial Structural and Functional Remodeling in Atrial Fibrillation, Computational and Statistical Framework to Model Tissue Shape and Mechanics, Seq-Scope: Microscopic Examination of Spatial Single Cell Transcriptome in Cell and Tissue Senescence
OpenAlex ID: W4417468422