MicroRNA-140 and the silencing of osteoarthritis

Abstract

MicroRNAs (miRNAs) have emerged as important modulators in development, tissue homeostasis, and diseases. In this issue of Genes & Development, Miyaki and colleagues (pp. 1173-1185) report that miR-140 is involved in the pathogenesis of osteoarthritis by regulating, at least in part, ADAMTS5. Moreover, mice lacking miR-140 are dwarf as a consequence of impaired chondrocyte proliferation. This study is the first in vivo demonstration that miR-140 has a critical and nonredundant role in cartilage development and homeostasis.

Figure 1.

Schematic representation of a synovial joint. The diarthrodial joint connects two bones, and it allows their reciprocal movements. Two bony epiphyses are surrounded by a layer of articular hyaline cartilage, and the joint cavity separates them. A tight joint capsule connects the ends of the bone, and its inner layer is made of synovial membrane that secretes synovial fluid into the joint cavity.

Figure 2.

Biogenesis and action of miRNAs. (Step 1) miRNAs are transcribed mainly by polymerase II. miRNA transcribed from genes (step 2a), polycistronic clusters (step 2b), or the intronic region (step 2c), called pri-miRNAs, and in the first two cases are then processed by the type III RNase Drosha. (Step 3) The newly formed stem–loop structure, pre-miRNA, is recognized by the XPO5, Ran-GTP complex, and is transported to the cytoplasm through the NPC. Dicer cleaves the loop (step 4), leaving a double-strand fragment, the miRNA:miRNA* duplex (step 5). The blue stand is the future mature miRNA, while the red strand is its antisense miRNA*. The duplex is then unwound and loaded into the miRISC complex (step 6) where it recognizes and anneals to its mRNA target 3′ UTR (step 7). The messenger RNA:miRISC complex mediates translational repression (step 8a) and mRNA decay (step 8b). For more details, see the text.