Journal of Molecular Signaling Updates

Journal of Molecular Signaling Updates - Volume 1

Genomic Signaling in Human Osteoarthritis-Affected Chondrocytes by HMGB1: Induction of Pro-/Anti-Inflammatory and Matrix Depleting Activity

Published on: 02 January 2016

Pages: 11-23

Ashok R. Amin and Abul B.M.M.K. Islam

1Department of Rheumatology, New York University-Hospital for Joint Diseases, New York, NY 10003, USA; 2Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; 3RheuMatrix Inc., Blacksburg, VA 24060, USA; 4Department of Biomedical Engineering, Virginia Tech, Blacksburg, VA 24060 and 5Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh

Abstract: Upregulation of multifunctional alarmin: High Mobility Group Protein 1 (HMGB1) is reported in arthritis-affected joints of man and mice; Furthermore, injection of HMGB1 into joints of mice also induced arthritis. However, the exact role(s,) of HMGB1 in human osteoarthritis (OA)-affected chondrocytes remain elusive. We, therefore, examined the genomics response to extracellular HMGB1 on human OA-affected chondrocytes by gene expression arrays to map all the signal transduction pathways and functions induced by HMGB1. Recombinant HMGB1 induced a burst of multifunctional cytokines, chemokines, nitric oxide [NO], receptors and signaling patterns. HMGB1 not only induced matrix-degrading metalloproteases [e.g. MMP-1, -12, -13] but downregulated mRNA expression of thirty key carbohydrates and proteins in the synthesis of the matrix. These include mannosidase, sulfotransferases, aggrecan, collagen, proteoglycan, heparan sulfate, laminin, syndecan, gelsolin, matrin, sarcoglycan, gremlin and cartilage oligomeric matrix protein in chondrocytes. KEGG database and pathway analysis revealed a ‘pro-inflammatory,' “inflammation resolution'” and “matrix depleting signature”-induced by HMGB1 in human chondrocytes. The inflammatory response to HMGB1 was propelled by signal transduction pathways associated with several cytokines, chemokines, Toll, NOD, signaling pathways, and complement and coagulation cascades. The HMGB1-induced chondrocytes also authenticated the essential role of the transcription factor: peroxisome proliferator-activated ϒ receptors (PPARϒ) signaling similar to that observed in the cartilage of PPARϒ-/- mice.KEGG pathway analysis also identified Juxtacrine-signaling molecules and pathways representing cell-cell, receptor-matrix interactions; Focal adhesion signaling pathways and ion transporters. HMGB1 induces inflammatory signaling events at the genomics level in chondrocytes concomitant with obstructing matrix synthesis. HMGB1 dictates the key signal transduction pathways-driving pathophysiological characteristics in human OA-affected chondrocytes, which includes inflammation and inflammation resolution, matrix degradation, endochondral ossification, inhibition of matrix synthesis and cartilage homeostasis depending on the location of the chondrocyte in the cartilage.

Keywords: HMGB1, Cartilage, Osteoarthritis, Matrix, Inflammation.

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