Osteoclast-specific Dicer gene deficiency suppresses osteoclastic bone resorption.
Osteoclasts are unique cells that resorb bone, and are involved in not only bone remodeling but also pathological bone loss such as osteoporosis and rheumatoid arthritis. The regulation of osteoclasts is based on a number of molecules but full details of these molecules have not yet been understood. MicroRNAs are produced by Dicer cleavage an emerging regulatory system for cell and tissue function. Here, we examine the effects of Dicer deficiency in osteoclasts on osteoclastic activity and bone mass in vivo. We specifically knocked out Dicer in osteoclasts by crossing Dicer flox mice with cathepsin K-Cre knock-in mice. Dicer deficiency in osteoclasts decreased the number of osteoclasts (N.Oc/BS) and osteoclast surface (Oc.S/BS) in vivo. Intrinsically, Dicer deficiency in osteoclasts suppressed the levels of TRAP positive multinucleated cell development in culture and also reduced NFATc1 and TRAP gene expression. MicroRNA analysis indicated that expression of miR-155 was suppressed by RANKL treatment in Dicer deficient cells. Dicer deficiency in osteoclasts suppressed osteoblastic activity in vivo including mineral apposition rate (MAR) and bone formation rate (BFR) and also suppressed expression of genes encoding type I collagen, osteocalcin, Runx2, and Efnb2 in vivo. Dicer deficiency in osteoclasts increased the levels of bone mass indicating that the Dicer deficiency-induced osteoclastic suppression was dominant over Dicer deficiency-induced osteoblastic suppression. On the other hand, conditional Dicer deletion in osteoblasts by using 2.3 kb type I collagen-Cre did not affect bone mass. These results indicate that Dicer in osteoclasts controls activity of bone resorption in vivo.
Mizoguchi
Fumitaka
F
Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10 Kanda Surugadai 2 chome, Chiyoda-ku, Tokyo 101-0062, Japan.
Izu
Yayoi
Y
Hayata
Tadayoshi
T
Hemmi
Hiroaki
H
Nakashima
Kazuhisa
K
Nakamura
Takashi
T
Kato
Shigeaki
S
Miyasaka
Nobuyuki
N
Ezura
Yoichi
Y
Noda
Masaki
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology*; D002452:Cell Count; D053487:DEAD-box RNA Helicases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D004722:Endoribonucleases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D053245:RANK Ligand / Q000494:pharmacology; D011859:Radiography; D043244:Ribonuclease III; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology
D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D053245:RANK Ligand; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases