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

Author(s)

Sartori-Cintra, Angelica Rossi ^[1] ; de Mara, Cristiane Sampaio ^[1] ; Argolo, Danielle L. ^[1] ; Coimbra, Ibsen Bellini ^[1]

Affiliation

^[1] State Univ Campinas UNICAMP, Dept Clin Med, Div Rheumatol, Lab Mol Biol Cartilage, Campinas, SP - Brazil

• Document type: Journal article
• Source: Clinics; v. 67, n. 1, p. 35-40, 2012.
• Web of Science Citations: 18

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-1 alpha) 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-1 alpha in human osteoarthritic chondrocytes by interleukin-1 beta (IL-1 beta) and insulin-like growth factors I (IGF-I) and II (IGF-II) and to determine the involvement of the phosphatidylinositol-3kinase (PI-3K) pathway in this process. METHODS: Human osteroarthritic chondrocytes were stimulated with IL-1 beta, 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-1 alpha expression was upregulated by IL-1 beta 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-1 alpha, whereas IGF-II had no effect on its expression. However, all of these stimuli exploited the PI-3K pathway. CONCLUSION: IL-1 beta upregulated the levels of HIF-1 alpha protein post-transcriptionally, whereas IGF-I increased HIF-1a at the transcript level. In contrast, IGF-II did not affect the protein or gene expression levels of HIF-1a. 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. (AU)

• FAPESP's process: 05/00985-0 - Participation of Hipoxia Inducible Factor 1 alpha (HIF-1 alpha) in the Interlukein-1 beta (IL-1 beta) and Tumor Necrose Factor (TNF-alpha) induced expression of collagen type II and aggrecan in chondrocytes under hypoxic and normoxic conditions
• Grantee: Angélica Rossi Sartori
• Support Opportunities: Scholarships in Brazil - Doctorate