RRC ID 19666
Author Hosaka Y, Saito T, Sugita S, Hikata T, Kobayashi H, Fukai A, Taniguchi Y, Hirata M, Akiyama H, Chung UI, Kawaguchi H.
Title Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development.
Journal Proc. Natl. Acad. Sci. U.S.A.
Abstract Here we examined the involvement of Notch signaling in the endochondral ossification process, which is crucial for osteoarthritis (OA) development. Intracellular domains of Notch1 and -2 were translocated into the nucleus of chondrocytes with their differentiation in mouse limb cartilage and in mouse and human OA articular cartilage. A tissue-specific inactivation of the Notch transcriptional effector recombination signal binding protein for Ig kappa J (RBPjκ) in chondroprogenitor cells of SRY-box containing gene 9 (Sox9)-Cre;Rbpj(fl/fl) mouse embryos caused an impaired terminal stage of endochondral ossification in the limb cartilage. The RBPjκ inactivation in adult articular cartilage after normal skeletal growth using type II collagen (Col2a1)-Cre(ERT);Rbpj(fl/fl) mice by tamoxifen injection caused resistance to OA development in the knee joint. Notch intracellular domain with the effector RBPjκ stimulated endochondral ossification through induction of the target gene Hes1 in chondrocytes. Among the Notch ligands, Jagged1 was strongly induced during OA development. Finally, intraarticular injection of N-[N-(3,5-diflurophenylacetate)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT), a small compound Notch inhibitor, to the mouse knee joint prevented OA development. The RBPjκ-dependent Notch signaling in chondrocytes modulates the terminal stage of endochondral ossification and OA development, representing an extracellular therapeutic target of OA.
Volume 110(5)
Pages 1875-80
Published 2013-1-29
DOI 10.1073/pnas.1207458110
PII 1207458110
PMID 23319657
PMC PMC3562777
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism Calcium-Binding Proteins / genetics Calcium-Binding Proteins / metabolism Cartilage / drug effects Cartilage / metabolism Cartilage / pathology Cell Line Cell Line, Tumor Chondrocytes / drug effects Chondrocytes / metabolism* Collagen Type II / genetics Collagen Type II / metabolism Dipeptides / pharmacology Fluorescent Antibody Technique HeLa Cells Homeodomain Proteins / genetics Homeodomain Proteins / metabolism Humans Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism Intercellular Signaling Peptides and Proteins / genetics Intercellular Signaling Peptides and Proteins / metabolism Jagged-1 Protein Knee Joint / drug effects Knee Joint / metabolism Knee Joint / pathology Membrane Proteins / genetics Membrane Proteins / metabolism Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Osteoarthritis / genetics Osteoarthritis / metabolism* Osteoarthritis / prevention & control Osteogenesis* Receptor, Notch1 / antagonists & inhibitors Receptor, Notch1 / genetics Receptor, Notch1 / metabolism* Receptor, Notch2 / antagonists & inhibitors Receptor, Notch2 / genetics Receptor, Notch2 / metabolism* Reverse Transcriptase Polymerase Chain Reaction SOX9 Transcription Factor / genetics SOX9 Transcription Factor / metabolism Serrate-Jagged Proteins Signal Transduction* Transcription Factor HES-1
IF 9.58
Times Cited 33
Mice Floxed RBP-J (RBRC01071)