Catabolic stress induces expression of hypoxia-inducible factor (HIF)-1α in articular chondrocytes: involvement of HIF-1α in the pathogenesis of osteoarthritis

Kazuo Yudoh,Hiroshi Nakamura,Tomohiro Kato,Kusuki Nishioka,Kayo Masuko-Hongo

doi:10.1186/ar1765

Abstract

Transcription factor hypoxia-inducible factor (HIF)-1 protein accumulates and activates the transcription of genes that are of fundamental importance for oxygen homeostasis – including genes involved in energy metabolism, angiogenesis, vasomotor control, apoptosis, proliferation, and matrix production – under hypoxic conditions. We speculated that HIF-1α may have an important role in chondrocyte viability as a cell survival factor during the progression of osteoarthritis (OA). The expression of HIF-1α mRNA in human OA cartilage samples was analyzed by real-time PCR. We analyzed whether or not the catabolic factors IL-1β and H2O2 induce the expression of HIF-1α in OA chondrocytes under normoxic and hypoxic conditions (O2 <6%). We investigated the levels of energy generation, cartilage matrix production, and apoptosis induction in HIF-1α-deficient chondrocytes under normoxic and hypoxic conditions. In articular cartilages from human OA patients, the expression of HIF-1α mRNA was higher in the degenerated regions than in the intact regions. Both IL-1β and H2O2 accelerated mRNA and protein levels of HIF-1α in cultured chondrocytes. Inhibitors for phosphatidylinositol 3-kinase and p38 kinase caused a significant decrease in catabolic-factor-induced HIF-1α expression. HIF-1α-deficient chondrocytes did not maintain energy generation and cartilage matrix production under both normoxic and hypoxic conditions. Also, HIF-1α-deficient chondrocytes showed an acceleration of catabolic stress-induced apoptosis in vitro. Our findings in human OA cartilage show that HIF-1α expression in OA cartilage is associated with the progression of articular cartilage degeneration. Catabolic-stresses, IL-1β, and oxidative stress induce the expression of HIF-1α in chondrocytes. Our results suggest an important role of stress-induced HIF-1α in the maintenance of chondrocyte viability in OA articular cartilage.

Highlights

The breakdown or absence of oxygen homeostasis is a hallmark of many common diseases, such as cancer, myocardial infarction, and arthritis
hypoxia-inducible factor (HIF)-1α mRNA expression in articular cartilage from patients with OA To clarify the expression of hypoxia-inducible factor 1α (HIF-1α) mRNA in human OA cartilage, the real-time PCR analysis for HIF-1α was performed with donor-matched pairs of intact and degenerated articular cartilage isolated from the same OA sample
Levels of HIF-1α mRNA in tthe aarrttiiccuullaarr ccaarrttiillaaggee ffrroomm ppaattiieennttsswwiitthhoosstteeooaarrtthhrriittiiss((OOAA)). (a)Representative x-ray film of knee joint and safranin-O staining for hypoxia-inducible factor 1α(HIF-1α) in the degenerated region and intact region of articular cartilage from a 66-year-old woman with OA

Summary

Introduction

The breakdown or absence of oxygen homeostasis is a hallmark of many common diseases, such as cancer, myocardial infarction, and arthritis. In most normal and tumor tissues, adaptation to hypoxic conditions is critical for successful tissue expansion [1,2]. In response to down-regulation of oxygen homeostasis, cells during hypoxic challenge transiently or chronically tolerate lowered oxygen levels by means of adaptive mechanisms [1]. Responses to hypoxia include a metabolic shift to anaerobic glycolysis as well as the initiation of neoangiogenesis via the expression of angiogenic factors to increase the opportunity for oxygen to reach the tissue [1,2,3,4,5]. Oxygen homeostasis and its down-regulation are involved in the pathogenesis of common diseases [3]

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Conclusion