Regulation of hypoxia-inducible factor-1α (HIF-1α) expression by interleukin-1β (IL-1β), insulin-like growth factors I (IGF-I) and II (IGF-II) in human osteoarthritic chondrocytes

Abstract

OBJECTIVE:Hypoxia-inducible factor 1 alpha regulates genes related to cellular survival under hypoxia. This factor is present in osteroarthritic chondrocytes, and cytokines, such as interleukin-1 beta, participate in the pathogenesis of osteoarthritis, thereby increasing the activities of proteolytic enzymes, such as matrix metalloproteinases, and accelerating cartilage destruction. We hypothesize that Hypoxia Inducible Factor-1 alpha (HIF-1α) can regulate cytokines (catabolic action) and/or growth factors (anabolic action) in osteoarthritis. The purpose of this study was to investigate the modulation of HIF-1α in human osteoarthritic chondrocytes by interleukin-1 beta (IL-1β) and insulin-like growth factors I (IGF-I) and II (IGF-II) and to determine the involvement of the phosphatidylinositol-3-kinase (PI-3K) pathway in this process.METHODS:Human osteroarthritic chondrocytes were stimulated with IL-1β, IGF-I and IGF-II and LY294002, a specific inhibitor of PI-3K. Nuclear protein levels and gene expression were analyzed by western blot and quantitative reverse transcription-polymerase chain reaction analyses, respectively.RESULTS:HIF-1α expression was upregulated by IL-1β at the protein level but not at the gene level. IGF-I treatment resulted in increases in both the protein and mRNA levels of HIF-1α, whereas IGF-II had no effect on its expression. However, all of these stimuli exploited the PI-3K pathway.CONCLUSION:IL-1β upregulated the levels of HIF-1α protein post-transcriptionally, whereas IGF-I increased HIF-1α at the transcript level. In contrast, IGF-II did not affect the protein or gene expression levels of HIF-1α. Furthermore, all of the tested stimuli exploited the PI-3K pathway to some degree. Based on these findings, we are able to suggest that Hypoxia inducible Factor-1 exhibits protective activity in chondrocytes during osteoarthritis.

Epigallocatechin-3-Gallate Inhibits IGF-I-Stimulated Lung Cancer Angiogenesis through Downregulation of HIF-1α and VEGF Expression

“…Recently, it has been shown that the expression of HIF-1α can be upregulated not only by hypoxia, but also by other nonhypoxic factors, such as the inactivation of tumor-suppressor genes (p53, pVHL, and PTEN [35,36,37]), activation of some viral oncoproteins (EBV and HPV-16 [38,39]), and challenge by IGF-I [40,41,42], etc. In the present study, the human NSCLC cell line A549 was used to investigate the effect of EGCG on the IGF-I-induced HIF-1α and VEGF expression and the proangiogenic activity of human lung cancer cells.…”

HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

“…Insulin-like growth factor 1, for instance, augmented the accumulation of HIF1A in normoxia in several cell types (Alam et al 2009, Sartori-Cintra et al 2012, Yu et al 2012. Reactive oxygen species (ROS) is another factor implicated in HIF1A accumulation.…”

Mechanism of Salviae Miltiorrhizae Radix et Rhizoma in the treatment of knee osteoarthritis based on network pharmacology

“…IL-17 can also promote bone resorption and collagen degradation; enhance the expression of chondrocytes MMP-9, MMP-13 and other metal matrix proteases; strengthen cartilage plate destruction and cartilage tissue decomposition; and induce joint destruction [69,70]. Studies have shown that IL-17 can enhance the formation of blood vessels in arthritic cartilage while activating and increasing vascular endothelial growth factor, aggravating in ammation, and causing bone brosis and hyperplasia [71]. Moreover, clinical studies have shown that the expression level of IL-17 in OA synovium and synovial uid is increased, and the increase in IL-17 level in OA synovial uid is related to the severity of OA [72][73][74].…”