HIF-1α in Osteoarthritis: From Pathogenesis to Therapeutic Implications

Abstract

Osteoarthritis is a common age-related joint degenerative disease. Pain, swelling, brief morning stiffness, and functional limitations are its main characteristics. There are still no well-established strategies to cure osteoarthritis. Therefore, better clarification of mechanisms associated with the onset and progression of osteoarthritis is critical to provide a theoretical basis for the establishment of novel preventive and therapeutic strategies. Chondrocytes exist in a hypoxic environment, and HIF-1α plays a vital role in regulating hypoxic response. HIF-1α responds to cellular oxygenation decreases in tissue regulating survival and growth arrest of chondrocytes. The activation of HIF-1α could regulate autophagy and apoptosis of chondrocytes, decrease inflammatory cytokine synthesis, and regulate the chondrocyte extracellular matrix environment. Moreover, it could maintain the chondrogenic phenotype that regulates glycolysis and the mitochondrial function of osteoarthritis, resulting in a denser collagen matrix that delays cartilage degradation. Thus, HIF-1α is likely to be a crucial therapeutic target for osteoarthritis via regulating chondrocyte inflammation and metabolism. In this review, we summarize the mechanism of hypoxia in the pathogenic mechanisms of osteoarthritis, and focus on a series of therapeutic treatments targeting HIF-1α for osteoarthritis. Further clarification of the regulatory mechanisms of HIF-1α in osteoarthritis may provide more useful clues to developing novel osteoarthritis treatment strategies.

Keywords: HIF-1α; chondrocytes; glycolysis; hypoxia; mitophagy; osteoarthritis.

FIGURE 1

Molecular mechanisms of HIF-1α degradation and stability. In normoxic conditions, with Fe²⁺ and 2-oxoglutarate, HIF-1α is hydroxylated by PHDs on Pro402 and Pro564, which allows the HIF-1α recognition by pVHL. Then HIF-1α protein is subject to rapid degradation by the pVHL mediated ubiquitin-proteasome pathway. In hypoxic conditions, due to the decreased activity of PHDs and inhibited hydroxylation and inactivation of pVHL, HIF-1α escapes proteasomal degradation. Stabilized HIF-1α binds with p300/CBP to increase transcriptional activity, which increases HIF-1α protein stability and thereby regulates transcriptional activation. bHLH, basic helix–loop–helix; HIF-1α, Hypoxia-inducible factor-1 α; ODDD, oxygen-dependent degradation domain; PAS, Per-ARNT-Sim homology; PHD, prolyl hydroxylase; pVHL, von Hippel-Lindau tumor suppressor protein; TAD-N, N-terminal transactivation domains; TAD-C, C-terminal transactivation domains.

FIGURE 2

Schematic representation of HIF-1α activation signaling pathway. Under hypoxia conditions, growth factors bind to receptor tyrosine kinase, and activate the PI3K and MAPK pathways. Then PI3K and MAPK activate their downstream AKT and MEK, which phosphorylate HIF-1α. Phosphorylated HIF-1α translocates to the nucleus, where it binds to HIF-1β and HREs to form the [(HIF-1α + HIF-1β) + HREs] complex. This functionally active transcriptional complex promotes regulation and expression of HIF-dependent adaptive genes, upregulates HIF-1α activity, and regulates many target receptors, such as BMP2, BNIP3, EPO, GLUT1, HMOX-1, iNOS, MMPs, SOX9, and VEGF. BMP2, bone morphogenetic protein 2; BNIP3, BCL2 and adenovirus E1B 19-kDa-interacting protein 3; EPO, erythropoietin; GLUT1, glucose transporter 1; HIF-1α, Hypoxia-inducible factor-1α; HMOX-1, heme oxygenase-1; HREs, hypoxia response elements; iNOS, inducible nitric oxide synthase; MMPs, matrix metalloproteinases; VEGF, vascular endothelial-derived growth factor.

FIGURE 3

Regulatory mechanisms and crucial influence of HIF-1α and hypoxia signaling on chondrocytes of OA. In less partial oxygen pressure, higher mechanical stress, and inflammation could exacerbate chondrocyte hypoxia, which will accumulate HIF-1α and increase transcriptional activity. Activated HIF-1α via regulating the apoptosis and autophagy of chondrocytes, the synthesis of extracellular matrix, glycolysis, mitochondrial function, and redox reactions of chondrocytes, maintains chondrogenic phenotype, protects articular cartilage and effectively alleviates the development of OA. ADAMTSs, a disintegrin and a metalloprotease with thrombospondin motifs; ATP, adenosine triphosphate; BNIP3, BCL2 and adenovirus E1B 19-kDa-interacting protein 3; EPO, erythropoietin; G6PD, glucose-6-phosphate dehydrogenase; GLUT1, glucose transporter 1; HIF-1α, Hypoxia-inducible factor-1 α; HREs, hypoxia response elements; IL-6, Interleukin-6; MMPs, matrix metalloproteinases; PEP, phosphoenolpyruvate carboxykinase; PDK1, pyruvate dehydrogenase kinase 1; PFK1, phosphoglycerate kinase 1; ROS, reactive oxygen species; UCP-3, uncoupling proteins-3; VEGF, vascular endothelial-derived growth factor.