Hypoxia potentiates the BMP-2 driven COL2A1 stimulation in human articular chondrocytes via p38 MAPK

• Published in: Osteoarthritis and cartilage 2016-05, Vol.24 (5), p.856-867
• Main Authors: Lafont, J.E, Poujade, F.-A, Pasdeloup, M, Neyret, P, Mallein-Gerin, F
• Format: Article
• Language: English
• Subjects: Anabolism; BMP signalling; Bone Morphogenetic Protein 2 - pharmacology; Cartilage, Articular - cytology; Cartilage, Articular - metabolism; Cell Hypoxia - physiology; Cells, Cultured; Cellular Biology; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrogenesis - drug effects; Collagen Type I - metabolism; Collagen Type II - biosynthesis; Collagen Type II - genetics; Collagen Type II - metabolism; Enzyme Activation - drug effects; Gene Expression Regulation - drug effects; Humans; Hypoxia; Life Sciences; p38 Mitogen-Activated Protein Kinases - metabolism; Rheumatology; Signal Transduction - drug effects; Subcellular Processes; Type II collagen production
• ISSN: 1063-4584; 1522-9653
• DOI: 10.1016/j.joca.2015.11.017

Summary Objective Since the biological effect of cartilage mediators is generally studied in a non-physiologic environment of 21% O2 , we investigated the effects of a chronic hypoxia on the capability of articular chondrocytes to respond to one anabolic stimulation. Design Human Articular Chondrocytes (HACs) were cultured under hypoxia and stimulated with the chondrogenic growth factor BMP-2. The phenotype of the chondrocytes was studied by RT-PCR, and the cartilage-specific type II collagen production and deposition were also examined by western immunoblot and immunofluorescence. The Bone Morphogenetic protein (BMP) signalling pathway was also analysed. Results BMP-2 is much more efficient to stimulate the expression of the cartilage-specific gene COL2A1 by HACs when cultured under hypoxia (1%O2 ) compared to normoxia (21%O2 ). Analysis of the BMP-activated signalling shows that the Smad pathway is inhibited under hypoxia, whereas p38 MAPK is activated, and is involved in a synergy between hypoxia and BMP signalling, thus contributing to the enhanced anabolic response. Conclusions Our study shows that hypoxia interplays with a chondrogenic factor and enhances the overall anabolic activity of the HACs. Alternatively to Hypoxia-Inducible Factor (HIF) signalling, and through a cross-talk with the BMP signalling which involves the p38 pathway, hypoxic stimulation markedly increases the capability of chondrocytes to produce the cartilage-specific type II collagen. Therefore our study provides new evidences of the multilayered effects of hypoxia in the anabolic functions of chondrocytes. This understanding may help promoting the anabolic function of articular chondrocytes, and thus improving their manipulation for cell therapy.