let-7 and miR-140 microRNAs coordinately regulate skeletal development.
MicroRNAs (miRNAs) play critical roles in multiple processes of skeletal development. A global reduction of miRNAs in growth plate chondrocytes results in defects in both proliferation and differentiation; however, specific microRNAs responsible for these defects have not been identified. In this study, we provide evidence that let-7 miRNAs and microRNA-140 (miR-140), among other miRNAs expressed in chondrocytes, play major roles in endochondral bone development. We overexpressed lin-28 homolog A (Lin28a) to inhibit let-7 miRNA biogenesis in growth plate chondrocytes. Lin28a overexpression efficiently and specifically reduced let-7 miRNAs and up-regulated let-7 target genes. However, unlike the previous notion that let-7 miRNAs inhibit proliferation and growth, suppression of let-7 miRNAs via Lin28a overexpression decreased proliferation in growth plate chondrocytes, likely through up-regulation of the let-7 target cell cycle regulators cell division cycle 34 (Cdc34) and E2F transcription factor 5 (E2F5). Deficiency of the chondrocyte-specific miRNA, miR-140, causes a differentiation defect in growth plate chondrocytes. Although either Lin28a overexpression or miR-140 deficiency alone caused only mild growth impairment, mice with both miR-140 deficiency and Lin28a overexpression in chondrocytes showed a dramatic growth defect. Deregulation of distinct processes in the absence of these miRNAs synergistically decreased the proliferating chondrocyte mass; miR-140 deficiency reduced differentiation into proliferating chondrocytes, whereas Lin28a overexpression decreased proliferation per se.
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Garyfallia
G
Papaioannou
Jennifer B
JB
Inloes
Yukio
Y
Nakamura
Elena
E
Paltrinieri
Tatsuya
T
Kobayashi
D000818:Animals; D001483:Base Sequence; D001846:Bone Development / Q000235:genetics / Q000502:physiology*; D016923:Cell Death; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D017931:DNA Primers; D025743:HMGA2 Protein / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics; D015854:Up-Regulation
D017931:DNA Primers; D025743:HMGA2 Protein; C488352:Lin-28 protein, mouse; C547828:MIRN140 microRNA, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse
chondrocyte differentiation; chondrocyte proliferation; mouse