Andrographolide inhibits the migration, invasion and matrix metalloproteinase expression of rheumatoid arthritis fibroblast-like synoviocytes via inhibition of HIF-1α signaling
Introduction
Rheumatoid arthritis (RA) is a chronic joint inflammatory disease with abnormal synovial hyperplasia and progressive destruction of cartilage and bone [1]. Fibroblast-like synoviocytes (FLSs) are key effector cells in the pathogenesis of RA [2]. They can produce massive amounts of degradative enzymes especially matrix metalloproteinases (MMPs), which contribute to the invasive growth of FLSs and subsequent joint destruction [3]. Activated RA-FLSs display tumor-like aggressive phenotypes, including anchorage-independent growth, apoptosis resistance, migration and invasion [4]. Modulation of the aggressive behaviors of FLSs has been suggested as an important strategy to treat RA [5].
The metabolically active synovium may require increased oxygen consumption [6]. However, vascular expansion does not compensate for the increased oxygen demand of the hyperplastic synovium, resulting in chronic hypoxia [7]. Synovial hypoxia frequently occurs in patients with RA, contributing to tendon rupture [8]. The cellular response to hypoxia is mainly driven by the transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) [9]. This is an upregulation of HIF-1α in RA patients [10]. HIF-1α is implicated in inflammatory cell recruitment and angiogenesis in the rheumatoid synovium [11], [12]. A specific deletion of HIF-1α in the myelod lineage cells results in a marked attenuation of synovitis and pannus formation [13]. These studies suggest an important role for HIF-1α in the pathogenesis of RA.
Andrographis paniculata (A. paniculata) is a traditional herbal medicine widely used in Asian countries, especially in both India and China [14]. A. paniculata shows therapeutic benefits in the treatment of several inflammatory disorders such as RA, laryngitis, and gastroenteritis [14], [15]. Andrographolide, a main constituent of A. paniculata, has been shown to possess a potent anti-inflammatory activity [16]. A prospective randomized placebo-controlled trial revealed that administration of an extract of A. paniculata (30% total andrographolides) can relieve several symptoms in RA patients [17]. An in vitro study demonstrated that andrographolide induces cell cycle arrest and apoptosis in human RA-FLSs [18]. However, the effect of andrographolide on the invasive phenotype of RA-FLSs remains unclear.
Previous studies revealed that andrographolide protects hypoxia-induced oxidative/nitrosative brain injury in mice [19] and down-regulates HIF-1α in human non-small cell lung cancer A549 cells [20]. Considering the important role of hypoxia in the pathogenesis of RA, it would be interesting to investigate the effects of andrographolide on hypoxia-induced pathological changes. In the present study, we used hypoxic RA-FLSs as a cell model to assess the effects of andrographolide on hypoxia-mediated invasiveness of RA-FLSs. The involvement of HIF-1α signaling in the action of andrographolide was also checked.
Section snippets
Patients and FLS isolation
Synovial tissue was obtained from 50 patients with RA during knee joint arthroscopy. All patients gave their written informed consent. The use of these tissues for research was approved by the ethics committee of Henan Provincial People's Hospital (Zhengzhou, China). The patients (12 men and 38 women) had a mean age of 51 ± 8 years and a mean disease duration of 11 ± 7 years. The median c-reactive protein level was 0.96 mg/dl (range: 0.22 to 3.05 mg/dl). The diagnosis of RA conformed to the 1987
Andrographolide attenuates the migration and invasion of RA-FLSs under hypoxic conditions
Transwell assays were employed to investigate the effects of andrographolide on the migration and invasion of RA-FLSs under hypoxic conditions. Hypoxia remarkably enhanced the migration and invasion of RA-FLSs (Fig. 1). However, the numbers of migrating RA-FLSs decreased in an andrographolide concentration-dependent manner (Fig. 1A). Similarly, andrographolide also significantly inhibited the invading ability of RA-FLSs in a concentration-dependent manner (Fig. 1B).
Andrographolide decreases hypoxia-induced upregulation of MMP-1, MMP-3 and MMP-9
Next, we examined the effects
Discussion
In the present study, we found that andrographolide suppressed hypoxia-mediated migration, invasion and upregulation of MMP-1, MMP-3, and MMP-9. Interestingly, andrographolide attenuated the expression of hypoxia-induced HIF-1α, a critical transcription factor for the cellular response to hypoxia, and decreased HIF-1α DNA binding activity. Overexpression of HIF-1α almost completely blocked andrographolide-induced inhibition of RA-FLS migration, invasion and MMP expression under hypoxic
Conclusions
Our results provide first evidence that andrographolide can suppress the migration and invasion of RA-FLSs induced by hypoxia. The anti-invasive activity of andrographolide in hypoxic RA-FLSs is largely mediated through inhibition of HIF-1α signaling. Further studies are warranted to explore the potential therapeutic benefits of andrographolide in the treatment of RA.
References (30)
- et al.
Synovial hypoxia as a cause of tendon rupture in rheumatoid arthritis
J. Hand. Surg. [Am.]
(2008) - et al.
HIF-1alpha is essential for myeloid cell-mediated inflammation
Cell
(2003) - et al.
In vitro and in vivo anti-inflammatory effects of andrographolide
Int. Immunopharmacol.
(2009) - et al.
Andrographolide down-regulates hypoxia-inducible factor-1α in human non-small cell lung cancer A549 cells
Toxicol. Appl. Pharmacol.
(2011) - et al.
Anti-invasive effects of celastrol in hypoxia-induced fibroblast-like synoviocyte through suppressing of HIF-1α/CXCR4 signaling pathway
Int. Immunopharmacol.
(2013) - et al.
The pathogenesis of rheumatoid arthritis
N. Engl. J. Med.
(2011) - et al.
Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors
Nat. Rev. Rheumatol.
(2013) - et al.
Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10
Ann. Rheum. Dis.
(2002) Rheumatoid arthritis: inflammation feeds inflammation—HDAC5 downregulation leads to activation of fibroblast-like synoviocytes in RA
Nat. Rev. Rheumatol.
(Feb 2015)- et al.
The role of histone deacetylases in rheumatoid arthritis fibroblast-like synoviocytes
Biochem. Soc. Trans.
(2013)
Role of hypoxia-inducible factor-1alpha in hypoxia-induced expressions of IL-8, MMP-1 and MMP-3 in rheumatoid fibroblast-like synoviocytes
Rheumatology (Oxford)
Hypoxia. The role of hypoxia and HIF-dependent signalling events in rheumatoid arthritis
Arthritis Res. Ther.
TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity
Proc. Natl. Acad. Sci. U. S. A.
Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint
Arthritis Rheum.
Upregulated hypoxia inducible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritis
Arthritis Res. Ther.
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