AMP-activated protein kinase (AMPK) activity negatively regulates chondrogenic differentiation

• Published in: Bone (New York, N.Y.) N.Y.), 2015-05, Vol.74, p.125-133
• Main Authors: Bandow, Kenjiro, Kusuyama, Joji, Kakimoto, Kyoko, Ohnishi, Tomokazu, Matsuguchi, Tetsuya
• Format: Article
• Language: English
• Subjects: Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Base Sequence; Cattle; Cell Differentiation - drug effects; Cells, Cultured; Chondrocyte; Chondrogenesis - drug effects; Egr-1; Embryo, Mammalian - cytology; Embryo, Mammalian - drug effects; Extremities - embryology; Gene Knockdown Techniques; Genes, Reporter; Glucose - pharmacology; Humans; Luciferases - metabolism; Metformin; Metformin - pharmacology; Mice, Inbred C57BL; Molecular Sequence Data; Orthopedics; Phosphorylation - drug effects; Protein Subunits - metabolism; Ribonucleotides - pharmacology; RNA, Small Interfering - metabolism; Sodium Selenite - pharmacology; Sox9; SOX9 Transcription Factor - genetics; SOX9 Transcription Factor - metabolism; Stem Cells - cytology; Stem Cells - drug effects; Transcriptional Activation - drug effects; Transcriptional Activation - genetics; Transferrin - pharmacology
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2014.12.001

Abstract Chondrocytes are derived from mesenchymal stem cells, and play an important role in cartilage formation. Sex determining region Y box (Sox) family transcription factors are essential for chondrogenic differentiation, whereas the intracellular signal pathways of Sox activation have not been clearly elucidated. AMP-activated protein kinase (AMPK) is a serine–threonine kinase generally regarded as a key regulator of cellular energy homeostasis. It is known that the catalytic alpha subunit of AMPK is activated by upstream AMPK kinases (AMPKKs) including liver kinase B1 (LKB1). We have previously reported that AMPK is a negative regulator of osteoblastic differentiation. Here, we have explored the role of AMPK in chondrogenic differentiation using in vitro culture models. The phosphorylation level of the catalytic AMPK alpha subunit significantly decreased during chondrogenic differentiation of primary chondrocyte precursors as well as ATDC-5, a well-characterized chondrogenic cell line. Treatment with metformin, an activator of AMPK, significantly reduced cartilage matrix formation and inhibited gene expression of sox6 , sox9 , col2a1 and aggrecan core protein ( acp ). Thus, chondrocyte differentiation is functionally associated with decreased AMPK activity.