Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development

Yoko Hosaka, Taku Saito, Shurei Sugita, Tomohiro Hikata, Hiroshi Kobayashi, Atsushi Fukai, Yuki Taniguchi, Makoto Hirata, Haruhiko Akiyama, Ung Il Chung, Hiroshi Kawaguchi

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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; Rbpjfl/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)-CreERT;Rbpjfl/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.

Original languageEnglish
Pages (from-to)1875-1880
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number5
DOIs
Publication statusPublished - 2013 Jan 29

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Keywords

  • Cartilage degradation
  • Skeletal development

ASJC Scopus subject areas

  • General

Cite this

Hosaka, Y., Saito, T., Sugita, S., Hikata, T., Kobayashi, H., Fukai, A., Taniguchi, Y., Hirata, M., Akiyama, H., Chung, U. I., & Kawaguchi, H. (2013). Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proceedings of the National Academy of Sciences of the United States of America, 110(5), 1875-1880. https://doi.org/10.1073/pnas.1207458110