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Do not overwork: cellular communication network factor 3 for life in cartilage

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Journal of Cell Communication and Signaling Aims and scope

Abstract

Cellular communication network factor (CCN) 3, which is one of the founding members of the CCN family, displays diverse functions. However, this protein generally represses the proliferation of a variety of cells. Along with skeletal development, CCN3 is produced in cartilaginous anlagen, growth plate cartilage and epiphysial cartilage. Interestingly, CCN3 is drastically induced in the growth plates of mice lacking CCN2, which promotes endochondral ossification. Notably, chondrocytes in these mutant mice with elevated CCN3 production also suffer from impaired glycolysis and energy metabolism, suggesting a critical role of CCN3 in cartilage metabolism. Recently, CCN3 was found to be strongly induced by impaired glycolysis, and in our study, we located an enhancer that mediated CCN3 regulation via starvation. Subsequent investigations specified regulatory factor binding to the X-box 1 (RFX1) as a transcription factor mediating this CCN3 regulation. Impaired glycolysis is a serious problem, resulting in an energy shortage in cartilage without vasculature. CCN3 produced under such starved conditions restricts energy consumption by repressing cell proliferation, leading chondrocytes to quiescence and survival. This CCN3 regulatory system is indicated to play an important role in articular cartilage maintenance, as well as in skeletal development. Furthermore, CCN3 continues to regulate cartilage metabolism even during the aging process, probably utilizing this regulatory system. Altogether, CCN3 seems to prevent “overwork” by chondrocytes to ensure their sustainable life in cartilage by sensing energy metabolism. Similar roles are suspected to exist in relation to systemic metabolism, since CCN3 is found in the bloodstream.

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Acknowledgements

The authors would like to thank Ms. Yoshiko Miyake for her secretarial assistance. This study was supported by JSPS KAKENHI Grant Nos. JP19H03817, JP20K20611, JP21H03105 and JP21K19603.

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Authors and Affiliations

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

    Satoshi Kubota, Kazumi Kawata, Takako Hattori & Takashi Nishida

  2. Department of Oral Biochemistry, Asahi University School of Dentistry, Mizuho, Japan

    Harumi Kawaki

  3. International CCN Society, Marseille, France

    Bernard Perbal

  4. Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences/Dental School, Okayama, Japan

    Masaharu Takigawa & Takashi Nishida

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  1. Satoshi Kubota
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  2. Harumi Kawaki
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  3. Bernard Perbal
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  4. Masaharu Takigawa
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  5. Kazumi Kawata
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Correspondence to Satoshi Kubota.

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Kubota, S., Kawaki, H., Perbal, B. et al. Do not overwork: cellular communication network factor 3 for life in cartilage. J. Cell Commun. Signal. 17, 353–359 (2023). https://doi.org/10.1007/s12079-023-00723-4

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