Review: The Role of MicroRNAs in Osteoarthritis and Chondrogenesis

Abstract

The etiology of osteoarthritis (OA) is complex, with genetic, developmental, biochemical, and biomechanical factors contributing to the disease process. Chondrocytes in articular cartilage must express appropriate genes to achieve tissue homeostasis, and this is altered in OA. One facet of the aberrant gene expression in OA is the replay of chondrocyte differentiation with the expression of genes associated with chondrocyte hypertrophy. The pattern of gene expression and the transcription factors that control chondrogenesis are known in some detail. Mechanisms that lead to altered gene expression in OA, however, are less well understood. MicroRNAs (miRNAs) are small noncoding RNAs that have recently been recognized as important regulators of gene expression in human cells. A number of miRNAs are regulated across chondrogenesis, and their function is beginning to be delineated. Similarly, miRNAs are differentially expressed in OA cartilage compared to normal tissue. MicroRNA-140 (miR-140), which is highly and selectively expressed in cartilage, has been the focus of much work to date, though the full gamut of its actions is still to be defined. Many other regulated miRNAs likely act as a network to control cartilage homeostasis, catabolism, and repair. Chondrocytes are the sole cell type in cartilage, and they produce and maintain the extracellular matrix (ECM) that gives the tissue its load-bearing function (1). Chondrocytes originate from mesenchymal stem cells (MSCs) through chondrogenic differentiation (2). Investigation of the mechanisms mediating chondrogenic differentiation of MSCs as well as regulation of their functions will contribute to a better understanding of skeletal development and new strategies for treating diseases such as OA. Chondrogenesis and chondrocyte function are highly regulated by transcription and growth factors. The SOX family members SOX9, L-SOX5, and SOX6 are necessary for chondrogenic differentiation (see, for example, ref. 3). Many family members of the bone morphogenetic protein (BMP) and transforming growth factor (TGF ) signaling pathways have also been shown to control chondrogenesis (2). An additional level of regulation mediated by miRNAs has been identified (4), and miRNAs may represent novel therapeutic targets for pharmacologic control of skeletal diseases. OA, the most prevalent degenerative joint disease, causes pain, tenderness, limitation of movement, and a variable degree of inflammation (5). OA is characterized by articular cartilage destruction due to an imbalance between the synthesis and degradation of ECM components, mainly type II collagen and the proteoglycan aggrecan. Matrix-degrading enzymes, e.g., the matrix metalloproteinases (MMPs) and ADAMTS, play important roles (1). The pathogenesis of OA is complex and poorly understood but involves the interaction of multiple factors, ranging from genetic predisposition to mechanical and environmental components (5). Studies are in progress to define molecular mechanisms underlying OA, including the roles of specific miRNAs in, e.g., phenotype shift, apoptosis, and regulation of gene expression in chondrocytes (6). MicroRNA-140, the major miRNA implicated in OA to date, plays a role in chondrogenesis and cartilage development (7–9). The knockout or overexpression of miR140 in vivo has profound effects on the development of OA (10,11). Other miRNAs appear to follow this pattern (see, for example, ref. 12), but it is likely that further miRNAs that contribute to OA play a role in, for example, mechanotransduction or inflammation. The utility of miRNAs may be in the diagnosis of OA, tissue Supported by the Vietnamese Ministry of Education and Training (Project 322 grant to Ms Le) and Arthritis Research UK (program grant 19424 to Drs. Swingler and Clark). Linh T. T. Le, MSc, Tracey E. Swingler, PhD, Ian M. Clark, PhD: University of East Anglia, Norwich, UK. Address correspondence to Ian M. Clark, PhD, Biomedical Research Centre, School of Biological Sciences, Norwich Research Park, University of East Anglia, Norwich NR4 7TJ, UK. E-mail: i.clark@uea.ac.uk. Submitted for publication September 11, 2012; accepted in revised form April 23, 2013.