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Novel role of CCN3 that maintains the differentiated phenotype of articular cartilage

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Abstract

Knowledge of the microenvironment of articular cartilage in health and disease is the key to accomplishing fundamental disease-modifying treatments for osteoarthritis. The proteins comprising the CCN Family are matricellular proteins with a remarkable relevance within the context of cartilage metabolism. CCN2 displays a great capability for regenerating articular cartilage, and CCN3 has been shown to activate the expression of genes related to articular chondrocytes and to repress genes related to endochondral ossification in epiphyseal chondrocytes. Moreover, mice lacking CCN3 protein have been shown to display ostearthritic changes in their knee articular cartilage. In this study, we employed a monoiodoacetic acid (MIA)-induced osteoarthritic model to investigate whether osteoarthritic changes in the cartilage are reciprocally accompanied by CCN3 down-regulation and an inducible overexpression system to evaluate the effects of CCN3 on articular chondrocytes in vitro. Finally, we also investigated the effects of exogenous CCN3 in vivo during the early stages of MIA-induced osteoarthritis. We discovered that CCN3 is expressed by articular chondrocytes in normal rat knees, whereas it is rapidly down-regulated in osteoarthritic knees. In vitro, we also discovered that CCN3 increases the proteoglycan accumulation, the gene expression of type II collagen, tenascin-C and lubricin, as well as the protein production of tenascin-C and lubricin in articular chondrocytes. In vivo, it was discovered that exogenous CCN3 increased tidemark integrity and produced an increased production of lubricin protein. The potential utility of CCN3 as a future therapeutic agent and possible strategies to improve its therapeutic functions are also discussed.

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Acknowledgements

The authors would like to thank Yoshiko Miyake for her invaluable secretarial assistance. DJ was a postdoctoral fellow supported by the Japanese Society for Promotion of Science (JSPS) when conducting the research described here. This study was supported by the Grant-in-aid for Scientific Research (B) [No.JP15H05014, No. JP 24390415] to MT and (C) [No. JP 15K11038] to EA and (C) [No.JP 25462886] to S.K. and Exploratory Research [No. JP 26670808] to MT from the Japan Society for the Promotion of Science (JSPS) and by the Grant in Aid attached to the JSPS Postdoctoral Fellowship for Overseas Researchers number 25/03412 to MT and DJ.

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Authors and Affiliations

  1. Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan

    Danilo Janune, Tarek Abd El Kader, Eriko Aoyama, Satoshi Kubota & Masaharu Takigawa

  2. Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan

    Danilo Janune, Takashi Nishida, Satoshi Kubota & Masaharu Takigawa

  3. Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

    Yasuhiko Tabata

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  1. Danilo Janune
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  2. Tarek Abd El Kader
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Correspondence to Satoshi Kubota or Masaharu Takigawa.

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Janune, D., Abd El Kader, T., Aoyama, E. et al. Novel role of CCN3 that maintains the differentiated phenotype of articular cartilage. J Bone Miner Metab 35, 582–597 (2017). https://doi.org/10.1007/s00774-016-0793-4

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  • DOI: https://doi.org/10.1007/s00774-016-0793-4

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