title: Early postnatal ablation of the microRNA-processing enzyme, Drosha, causes chondrocyte death and impairs the structural integrity of the articular cartilage.
abstract: OBJECTIVE
  In growth plate chondrocytes, loss of Dicer, a microRNA (miRNA)-processing enzyme, causes defects in proliferation and differentiation, leading to a lethal skeletal dysplasia. However roles of miRNAs in articular chondrocytes have not been defined in vivo. To investigate the role of miRNAs in articular chondrocytes and to explore the possibility of generating a novel mouse osteoarthritis (OA) model caused by intrinsic cellular dysfunction, we ablated Drosha, another essential enzyme for miRNA biogenesis, exclusively in articular chondrocytes of postnatal mice.
  
  
  METHODS
  First, to confirm that the essential role of miRNAs in skeletal development, we ablated the miRNA biogenesis pathway by deleting Drosha or DGCR8 in growth plate chondrocytes. Next, to investigate the role of miRNAs in articular cartilage, we deleted Drosha using Prg4-CreER(T) transgenic mice expressing a tamoxifen-activated Cre recombinase (CreER(T)) exclusively in articular chondrocytes. Tamoxifen was injected at postnatal days, 7, 14, 21, and 28 to ablate Drosha.
  
  
  RESULTS
  Deletion of Drosha or DGCR8 in growth plate chondrocytes caused a lethal skeletal defect similar to that of Dicer deletion, confirming the essential role of miRNAs in normal skeletogenesis. Early postnatal Drosha deletion in articular chondrocytes significantly increased cell death and decreased Safranin-O staining. Mild OA-like changes, including surface erosion and cleft formation, were found in male mice at 6 months of age; however such changes in females were not observed even at 9 months of age.
  
  
  CONCLUSIONS
  Early postnatal Drosha deficiency induces articular chondrocyte death and can cause a mild OA-like pathology.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: tkobayashi1@mgh.harvard.edu.
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: GPAPAIOANNOU@mgh.harvard.edu.
authors.forename: G
authors.initials: G
authors.lastname: Papaioannou
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: FMIRZAMOHAMMADI@mgh.harvard.edu.
authors.forename: F
authors.initials: F
authors.lastname: Mirzamohammadi
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: eKozhemyakina@dresourcesgroup.com.
authors.forename: E
authors.initials: E
authors.lastname: Kozhemyakina
authors.affiliation: Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Minjie.Zhang@childrens.harvard.edu.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: blellochr@stemcell.ucsf.edu.
authors.forename: R
authors.initials: R
authors.lastname: Blelloch
authors.affiliation: Genomics and Immunology Laboratory, St. Vincent's Institute of Medical Research, and Department of Medicine, University of Melbourne, Fitzroy, VIC 3065, Australia. Electronic address: mchong@svi.edu.au.
authors.forename: M W
authors.initials: MW
authors.lastname: Chong
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001848:Bone Diseases, Developmental / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002358:Cartilage, Articular / Q000473:pathology*; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D019902:Chondrocytes / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D006132:Growth Plate / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D010003:Osteoarthritis / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013629:Tamoxifen
chemical_list: C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D013629:Tamoxifen; C513400:Drosha protein, mouse; D043244:Ribonuclease III
keywords: Articular cartilage; Chondrocyte; Drosha; Osteoarthritis; Prg4; microRNA