Role of HIF-1α in Rheumatoid Arthritis: A Mini Review

Abstract

Rheumatoid arthritis is an autoimmune disease and also a member of arthritis that can cause joint pain and damage in the body. The pathogenicity of (RA) is not fully elucidated due to its complexity but based on the available data interplay between environmental and genetic factor was reported. Therefore this Review is going to highlight the molecular pathways activated through the influence of Hypoxia inducible factor one alpha (HIF-1alpha) in (RA) and how these pathways might interact with inflammatory signaling, angiogenesis, as well as cartilage destruction via activation of some relevant genes in RA. In conclusion, this review highlighted the role of HIF-1alpha in pathogenesis of RA

Keywords

Rheumatoid arthritis, Hypoxia Inducible factor one alpha, Pathogenesis and Inflammation

Introduction

Rheumatoid arthritis (RA) can be described as a severe chronicautoimmunedisease characterized by joint inflammation, destruction of cartilage and the presence of autoantibodies [1,2]。Statistically, RA affects 1% of the world’s population [3]。RA is a ubiquitous disease although in urban area of some countries the prevalence seems to be less [4]。

Pathogenicity of RA comes from both genetic and environmental factors and leads to the response of innate and adoptive immunity of the organism and to systematic inflammation [5]。With this, researchers have divided the pathogenicity into chronic and early and suggested that both have more similarities than differences [6]。Many investigators believed that an appropriate genetic background combined with stochastic events, such as activation of innate immunity, can serve as the trigger for RA [7]。Yet several aspects need to be considered [5]。Moreover, there are different pathogenic factors in RA, such as low oxygen partial pressure (synovial hypoxia), which is highly considered as a potential pathogenic factor and also constant feature of RA [3]。

Hypoxia occur when there is imbalance between demand and supply of oxygen [1], this can results in tissue dysfunction and even death. Thus under hypoxic condition, cell activate genes in order to control the hypoxic environment [5], among these genes, we have Hypoxia inducible factor (HIF) as one of the key regulator of the tissue hypoxia [8]。Three different HIF-alpha subunits have been described to date, with the greatest amount of research carried out on the two most closely related HIF-alpha-subunits and were found to play fundamental roles as mediators of transcriptional responses to hypoxia [9,10]。Thus, the aim of this review is to highlight different regulatory patterns of HIF-1α on RA pathogenesis through influence of some regulatory genes under hypoxic condition, as it has been found in other types of arthritis such as osteoarthritis, different types of cancer and Retinopathy.

HIF-1α Structure

Structurally, HIF-1α protein possesses N-terminal transactivation domain (N- TAD) and C-terminal transactivation domain (C-TAD). It has polypeptide chain of 826-amino-acid [11]。Half parts of the C-terminal is involved in activation of the transcriptional process therefore the C-TAD particularly interacts with CBP/p300 which is (acting as co-activators) to activate genetranscription. The association of HIF-1α with co-activators CBP/p300 is inhibited due to hydroxylation of an asparagine residue in the C-TAD [12]。

Furthermore, HIF-1α also possesses an oxygen-dependent degradation domain called (ODDD) that mediates oxygen-regulated stability [1]。In the presence of normal oxygen tension levels (normoxia), HIF-1α become hydroxylase in a proline residue within the same domain, which subsequently binds to ubiquitin and it is degraded in the proteasome [13]。However, under hypoxic conditions, hydroxylation is inhibited and HIF-1α accumulates in the cytoplasm, later become phosphorylated and changes it is territory moving to the nucleus in order to activate transcription of some of it is target genes, such as vascularendothelialgrowth factor (VEGF), Insulin-like growth factor type 2 (IGF2) and some oxide synthase 2 (NOS2) [11]。The stability of this protein is also enhanced through truncation of the HIF-1α at amino acid 390 which resulted in a constitutively stable protein, these explain the concept of HIF-1α half-life modulated by oxygen concentration as well as sequences from carboxyl terminal domain to amino acid 390 [10]。

HIF-1α Expression in RA

HIF-1α is detected in the sub-lining layer in lower amount and strongly expressed in the intimal layer of the RA synovium, including in residentmacrophages[14]。HIF-1α was found up regulated in RA fibroblast [15]。But a recent research shows that, celastrol, a triterpine compound with an antioxidant and anti-inflammatory activity, inhibits hypoxia-induced migration and invasion of synovial fibroblasts through suppression of the HIF-1alpha-mediated CXCR4 in RA [16]。

In addition, HIF-1α also promotes the activation of some signaling pathways and controls IL-33 production by fibroblasts, which in turn induces expression of HIF-1α and generates a regulatory cycle that perpetuates inflammation in RA [3]。Furthermore, a recent study found evidence for a functional interaction of HIF-1α and some other genes such as Notch-3, and STAT-1 to regulate pro-inflammatory mechanisms in RA synovial fibroblast during hypoxia [17](Figure 1).

HIF-1α and Inflammation in RA

Cramer et al. shows the first evidence of HIF-1α participation in the inflammatory process by knockout of HIF-1α in macrophages which result in reduction of disease severity in different models of both acute and chronic inflammation. Using fish model, they also demonstrate the role of HIF-1α in neutrophil inflammation, by showing the reduction of inflammation as a result of HIF- 1α activation. Both genetic manipulation and pharmacological approaches suggested that the activation of HIF-1α delays the resolution of inflammation and leads to reduction in neutrophil apoptosis and also increase the retention of neutrophils at the site of injury, therefore delays retention of the neutrophils [8,18]。

Regulatory role of HIF-1α in inflammation was also shown in knock-out experiment in mice. The result shows significant reduction in synovial inflammation, pannus formation,cartilagedestruction and histological improvement [19]。Moreover, PI3 kinase/Akt-mediated HIF-1α expression has been shown to play a critical role in hypoxia-induced epithelialmesenchymal transition (EMT), phenotype transformation of fundamental laparoscopic of surgery (FLS), synovial hyperplasia, and inflammatory cell infiltration in vivo in the CIA model [20]。Also, Inhibition of HIF-1α signaling attenuated hypoxia-induced invasiveness of activated FLS from the synovium of RA patients [21]。Synovitis happens to be one of the most important characteristic of RA. It has synovium which consist of two layers, the initial lining called (intima) and an underlining loose connective tissue called sub-lining or (subintima) layer [22]。It was found that the architecture of the affected synovium is distorted and changes in shape as RA progresses. That result in an increase in proliferation in the synovial cell lining to about 10-15 layers and also the sub-intimal layer become excessively infiltrated by immune cells which resulted in neovascularization [6]。

In addition, a new research indicates that there are also inflammatory factors that are found up regulating the expression of HIF-1α [23], such as IL-1, IL-33 and TNF-alpha [24]。Another chemokine called SDF-1 was also found up-regulated in response to hypoxia in RA [14]。It is Co-expression with HIF-1α has been identified in both synovial tissue explants and synovial fibroblasts [14]。In addition it is also involved in a number of pathogenic events such as increased synovitis,angiogenesis, bone erosion, and cartilage destruction [25]。

Up-regulation of HIF-1α has also been shown to significantly enhances the expression of IL-33, which is then able to form a complex of HIF-1alpha/IL-33 regulatory circuit which increases HIF-1α expression [26]。此外,据报道,overexpression of HIF-1α does enhance RASF-mediated expansion of inflammatory Th1 and Th17 cells, as well as enhance inflammatory cytokine expression in polyIC-stimulated RASF thereby inducing a shift toward a pro-inflammatory state in RA [27]。

Role of HIF-1α in Angiogenesis in RA

This is the development of new vessels; it is an important process in health and disease. The perpetuation of neovascularization in inflammatory diseases, such as rheumatoid arthritis may promote the ingress of inflammatory cells into synovium [28]。The regulation of angiogenesis by hypoxia is an important component of homeostatic control mechanisms. It links cardio-pulmonaryvascular oxygen supply to metabolic demand in local tissue [29]。Therefore, in RA, the synovial angiogenesis is likely due to the hypoxia and it was found that nutrients are also being supplied to the pannus do to increase in blood supply and relatively that also increase transportation of immune cells to the very site of inflammation [17]。In addition, an indication of it HIF-1α role in angiogenesis was found in local vein, it became up-regulated in the local vein wall and promotes angiogenesis to re-open the veins and resolve the blood clot [30]。

Furthermore, expression of a wild type HIF-1α in ischemic tissue may stimulate angiogenesis. This has been demonstrated for gene therapy with VEGF and other angiogenic factors [31]。But may also promote survival of ischemic cells during the period when vascularization is in progress. Research in this field of rheumatology holds out the prospect of understanding fundamental aspects of development andphysiology. While at the same time, it is also providing novel therapeutic approaches to the most common causes of mortality in the western world [32]。However it is association with an angiogenic factors (VEGF) was found by increasing the expression of VEGF in the inflammatory joint regions, as well as in cells that are derived from RA synovium [33]。Also stromal cell derived factor 1 (SDF1, also known as CXC-chemokine ligand 12) has dual role, both as pro-angiogenic, as well as being a member of the CXC family of chemokine [9]。

Cartilage Destruction and Borne Errosion in RA Influenced by HIF-1α

HIF-1α serves as a survival factor on healthy cartilage [24], as well as maintaining cartilage homeostasis. It was found that TSA significantly decreased the expression of some metalloproteinase (MMP-2 and MMP-9). In RA FLSs induced by hypoxia and also hypoxia-induced invasion was significantly suppressed by TSA treatment [34]。With all these, the researchers concluded that, their data indicate role of TSA in an anti-invasive activity in hypoxic RA, largely through down-regulation of MMP-2 and MMP-9 [21]。In addition, angiopoietin-like 4 (ANGPLT4) is overexpressed in RA osteoclasts in a HIF-1α dependent manner [35], especially in RA synovial tissue which is also sources of ANGPLT4 to promote bone desorption [17]。Moreover HIF-1α expression was found not significantly involve in MMP-1 and MMP-13 of FLS under nomoxic condition in RA, rather under hypoxic condition via IL-1β stimulation [36](Figure 2).

Conclusion

In conclusion, HIF-1α was found playing roles in RA inflammation, angiogenesis, cartilage destruction and bone erosion, through activation of relevantgenes. Hence pathogenicity of RA is still not fully clear, although inflammation and angiogenesis are identified as essential players. Identification of new SNPs that help HIF-1α during it is transcriptional activity on the mentioned cytokines genes, chemokine, pro-angiogenic factors, metalloproteinase and other proteins that are not yet been reported in RA cases is worth doing. Therefore HIF-1α seems to be a key molecule in RA pathogenesis and a promising therapeutic target in the context of RA.

Recommendations

A research needs to be taken with aim of observing the effect of HIF-1α SNPs that are found at exon regions on RA patients together with any of cytokines, pro-angiogenic factors, metalloproteinase and or chemokine in order to see their clear activating pathways with respect to inflammation, angiogenesis, borne erosion and cartilage destructions in RA patients as it was done in some other Arthritis classes.

References

1. Rejholec V. Rheumatic diseases. Casopis Lekaru Ceskych. 1979;118:1415-1419.
2. Giatromanolaki,等。调节缺氧感应ible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther. 2003;5:R193-R201.
3. Quiñonez-Flores CM et al. Hypoxia and its implications in rheumatoid arthritis. Journal of Biomedical Science. 2016;23:62.
4. Hameed K, et al. The association of HLA-DRB genes and the shared epitope with rheumatoid arthritis in Pakistan. Arthritis Rheum. 1997;36:1184-1188.
5. Picerno, et al. One year in review: The pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 2015;33:551-558.
6. McInnes IB and Schett G. The pathogenesis of rheumatoid arthritis. Ne N Engl J Med. 2011;365:2205-2219.
7. Firestein, G. S. Pathogenesis of rheumatoid arthritis: How early is early?. Arthritis Res Ther. 2005;7:157-159.
8. Sun G and Peng H. HIF-1α-induced microRNA-210 reduces hypoxia-induced osteoblast MG-63 cell apoptosis. Journal Bioscience, Biotechnology, and Biochemistry. 2015;79:1232-1239.
9. Kaelin WG and Ratcliffe PJ. Oxygen sensing by metazoans: The central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393-402.
10. Brouwer E, et al. Hypoxia inducible factor-1-alpha (HIF-1α) is related to both angiogenesis and inflammation in rheumatoid arthritis. Clin Exp Rheumatol. 2009;27:945-951.
11. Schwab A, et al. Invited review. Cell. 2001;2:1474-1480.
12. Kant R, et al. Prolyl 4 hydroxylase: A critical target in the pathophysiology of diseases. Korean J Physiol Pharmacol. 2013;17:111-120.
13. Heyman SN, et al. Hypoxia-inducible factors and the prevention of acute organ injury. Critical Care. 2011;15:209.
14. Hollander AP, et al. Expression of hypoxia-inducible factor 1α by macrophages in the rheumatoid synovium: Implications for targeting of therapeutic genes to the inflamed joint. Arthritis and Rheumatism. 2001;44:1540-1544.
15. Ryan HE, et al. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 1998;17:3005-3015.
16. Yang L, et al.Celastrusorbiculatusextract triggers apoptosis and autophagy via PI3K/Akt/mTOR inhibition in human colorectal cancer cells. Oncology Letters. 2016;12:3771-3778.
17. Swales C, et al. Angiopoietin-like 4 is over-expressed in rheumatoid arthritis patients: Association with pathological bone resorption. PLoS ONE. 2014b; 9: e109524.
18. Elks PM, et al. Activation of hypoxia-inducible factor-1α (HIF-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Blood. 2011; 118:712-722.
19. Cramer T, et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell. 2003;112:645-657.
20. Hu K, et al.Atrazine promotes RM1 prostate cancer cell proliferation by activating STAT3 signaling. Int J Onco. 2016;48:2166-2174.
21. Zhang Y and Zhang B. Trichostatin A, an inhibitor of histone deacetylase, inhibits the viability and invasiveness of hypoxic rheumatoid arthritis fibroblast-like synoviocytesvia PI3K/Aktsignaling. J Biochem Mol Toxicol. 2016;30:163-169.
22. Smith MD. The Normal Synovium. Open Rheumatol J. 2011;5:100-106.
23. Hua S and Dias TH. Hypoxia-Inducible Factor (HIF) as a target for novel therapies in rheumatoid arthritis. Front Pharmacol. 2016;7:1-9.
24. Singh JA, et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2016;68:1-25.
25. Villalvilla A, et al. SDF-1 signaling: A promising target in rheumatic diseases. Expert opinion on therapeutic targets. 2014;18:1077-1087.
26. 胡F, et al。低氧诱导因子- 1α和国米leukin 33 form a regulatory circuit to perpetuate the inflammation in rheumatoid arthritis. PLoS ONE. 2013;8: e72650.
27. 胡F, et al。Toll-like receptors expressed by synovial fibroblasts perpetuate Th1 and Th17 cell responses in rheumatoid arthritis. PLoS ONE. 2014;9:e100266.
28. Szekanecz Z and Koch AE. Mechanisms of disease: Angiogenesis in inflammatory diseases. Nature Clinical Practice Rheumatology. 2007;3:635-643.
29. 副大臣K和西门GL, angiogenesi监管s by hypoxia-inducible factor 1. Crit Rev Oncol Hematol. 2006;59:15-26.
30. Huang LE and Bunn HF. Hypoxia-inducible factor and its biomedical relevance. J of Biol Chem. 2003;278:19575-19578.
31. Vatner SF. FGF induces hypertrophy and angiogenesis in hibernating myocardium. Circulation Research. 2005;96:705-707.
32. Semenza GL. Hypoxia-inducible factor 1: Master regulator of O2 homeostasis. CurrOpin Genet Dev. 1998;8:588-594.
33. Koch AE, et al. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol. 1994;152:4149-4156.
34. Pfander D et al. The role of HIF-1α in maintaining cartilage homeostasis and during the pathogenesis of osteoarthritis. Arthritis Res Ther. 2006;8:104.
35. Larsen H, et al. Differential effects of Th1 versus Th2 cytokines in combination with hypoxia on HIFs and angiogenesis in RA. Arthritis Res Ther. 2012;14:R180.
36. Lee YA, et al. Hypoxia differentially affects IL-1β-stimulated MMP-1 and MMP-13 expression of fibroblast-like synoviocytes in an HIF-1α-dependent manner. Rheumatology. 2012;51:443-450.