Hypoxia-Inducible Factor and Oxidative Stress in Tendon Degeneration: A Molecular Perspective

Abstract

Tendinopathy is a debilitating condition marked by degenerative changes in the tendons. Its complex pathophysiology involves intrinsic, extrinsic, and physiological factors. While its intrinsic and extrinsic factors have been extensively studied, the role of physiological factors, such as hypoxia and oxidative stress, remains largely unexplored. This review article delves into the contribution of hypoxia-associated genes and oxidative-stress-related factors to tendon degeneration, offering insights into potential therapeutic strategies. The unique aspect of this study lies in its pathway-based evidence, which sheds light on how these factors can be targeted to enhance overall tendon health.

Keywords: degenerative disorders; hypoxia; oxidative stress; tendinopathy; tendon disorders.

Figure 1

HIF-1α under intermittent hypoxia and normoxia. NOX, NADPH oxidase; ROS, Reactive oxygen species; IP3, Inositol 1,4,5-trisphosphate; DAG, Diacylglycerol; CAM, Calcium/calmodulin; CAMK, Ca²⁺/calmodulin-dependent protein kinase; mTOR, Mammalian target of rapamycin; PI3K, Phosphoinositide 3 kinase; AKT, Protein kinase B; mTORC1, Mammalian target of rapamycin complex 1; MLST8, Mammalian lethal with SEC13 protein 8; PRAS40, Proline-rich Akt substrate of 40 kDa; P70s6k, Ribosomal protein S6 kinase beta-1; eIF4E, Eukaryotic translation initiation factor 4E; 4E-BP1, Eukaryotic translation initiation factor 4E binding protein 1; rps6, Ribosomal protein S6; HIF-1α, Hypoxia-inducible factor 1-alpha; OH, Hydroxide; CUL2, Cullin-2; Rbx1, Ring-Box 1; E2, Ubiquitin-conjugating enzymes; E3, E3 ubiquitin ligases; VHL, Von Hippel–Lindau.

Figure 2

HIF-1α activation regulates several key cellular processes. HIF-1α, Hypoxia-inducible factor 1-alpha; HIF-1β, Hypoxia-inducible factor 1-beta; POLIII, Polymerase 3; CBP/P300, Histone acetyltransferases CBP and p300; p300, E1A binding protein; CBP, CREB-binding protein; mRNA, Messenger RNA; PHD, Prolyl hydroxylase domain; FIH-1, Factor inhibiting hypoxia-1; HRE, Hypoxia response element; Ub, Ubiquitination; OH, Hydroxide; O₂, Oxygen; Fe²⁺, Iron(II) ion; α-KG, α-ketoglutarate; EPO, Erythropoietin; TF, Transferrin; TFRC, Transferrin receptor; iNOS, Inducible nitric oxide synthase; eNOS, Endothelial nitric oxide synthase; HMOX1, Heme Oxygenase; ANP, Atrial natriuretic peptide; END1, Endothelin1; FLT1, Fms related receptor tyrosine kinase 1; VEGF, Vascular endothelial growth factor; ANGPT1, Angiopoietin-1; Tie-2, Angiopoietin-1 Receptor; PAI-1, Plasminogen activator inhibitor 1; TIMP-1, Tissue inhibitor of metalloproteinases.

Figure 3

Regulation of the hypoxia factor HIF-1α may promote tendon repair in chronic tendon disorders. HIF-1α, Hypoxia-inducible factor 1-alpha; BCL2, B-cell lymphoma/leukemia-2; SCX, Scleraxis; MMP-3, Matrix Metalloproteinase 3; MKX, Mohawk X; EPO, Erythropoietin; ANGPT2, Angiopoietin 2; VEGFD, Vascular endothelial growth factor D; VEGFC, Vascular endothelial growth factor C; VEGFB, Vascular endothelial growth factor B; BNIP3, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3; BNIP3L, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like; TIMP1, Tissue inhibitor of metalloproteinases 1; TNMD, Tenomodulin.

Figure 4

HIF-1α regulates ROS and worsens tendon health during TP. HIF-1α, Hypoxia-inducible factor 1-alpha; MMP-3, Matrix Metalloproteinase 3; SCX, Scleraxis; TNMD, Tenomodulin; TIMP1, Tissue inhibitor of metalloproteinases 1; ANGPT2, Angiopoietin 2; MMP-9, Matrix Metalloproteinase 9; MMP-2, Matrix Metalloproteinase 2; TNC, Tenascin C; NOX1, NADPH Oxidase 1; NOX4, NADPH Oxidase 4; SOD1, Superoxide dismutase 1; GPx3, Glutathione Peroxidase 3.