Cartilage mechanobiology and transcriptional effects of combined mechanical compression and IGF-1 stimulation on bovine cartilage explants

Abstract

Background: Investigators have focused on mechano-regulation of upstream signaling and responses at the level of gene transcription, protein translation and post-translational modifications. Intracellular pathways including those involving integrin signaling, mitogen activated protein kinases (MAPKs), and release of intracellular calcium have been confirmed in several laboratories. Studies with IGF-1: Insulin-like growth factor-I (IGF-1) is a potent anabolic factor capable of endocrine and paracrine/autocrine signaling. Previous studies have demonstrated that mechanical compression can regulate the action of IGF-1 on chondrocyte biosynthesis in intact tissue; when applied simultaneously, these stimuli act by distinct cell activation pathways. Our objectives were to elucidate the extent and kinetics of the chondrocyte transcriptional response to combined IGF-1 and static compression in cartilage explants. Discussion: Clustering analysis revealed five distinct groups. TIMP-3 and ADAMTS-5, MMP-l and IGF-2, and IGF-1 and Collagen II, were all robustly co-expressed under all conditions tested. In comparing gene expression levels to previously measured aggrecan biosynthesis levels, aggrecan synthesis is shown to be transcriptionally regulated by IGF- 1, whereas inhibition of aggrecan synthesis by compression is not transcriptionally regulated.

(cont.) Conclusion: Many genes measured are responsive the effects of IGF-1 under 0% compression and 50% compression. Clustering analysis revealed strong co-expressed gene pairings. IGF-1 stimulates aggrecan biosynthesis in a transcriptionally regulated manner, whereas compression inhibits aggrecan synthesis in a manner not regulated by transcriptional activity.