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  • Review Article
  • Published:

Joint diseases: from connexins to gap junctions

Nature Reviews Rheumatology volume 14, pages 42–51 (2018)Cite this article

Subjects

Key Points

  • Multiple connexins are expressed in musculoskeletal tissues, including in joints

  • Gap-junctional intercellular communication contributes to interconnected cell syncytium, which connect various cell types within joints

  • Connexin dysfunction might contribute to joint disease

  • Emerging data suggest that connexins might be novel targets for treating joint disease

Abstract

Connexons form the basis of hemichannels and gap junctions. They are composed of six tetraspan proteins called connexins. Connexons can function as individual hemichannels, releasing cytosolic factors (such as ATP) into the pericellular environment. Alternatively, two hemichannel connexons from neighbouring cells can come together to form gap junctions, membrane-spanning channels that facilitate cell–cell communication by enabling signalling molecules of approximately 1 kDa to pass from one cell to an adjacent cell. Connexins are expressed in joint tissues including bone, cartilage, skeletal muscle and the synovium. Indicative of their importance as gap junction components, connexins are also known as gap junction proteins, but individual connexin proteins are gaining recognition for their channel-independent roles, which include scaffolding and signalling functions. Considerable evidence indicates that connexons contribute to the function of bone and muscle, but less is known about the function of connexons in other joint tissues. However, the implication that connexins and gap junctional channels might be involved in joint disease, including age-related bone loss, osteoarthritis and rheumatoid arthritis, emphasizes the need for further research into these areas and highlights the therapeutic potential of connexins.

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Figure 1: Connexins, connexons, hemichannels and gap junctions.
Figure 2: Connexins in bone.
Figure 3: Connexins in cartilage.
Figure 4: Connexins in synovium.

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Acknowledgements

The work of the authors is supported by grants from the NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases, R01AR068132-17 (to H.J.D.), R01AR 064255–05 (to D.C.G.) and a Virginia Commonwealth University School of Engineering Foundation Endowment (to H.J.D.).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, 23284, Virginia, USA

    Henry J. Donahue

  2. Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California at Davis, One Shields Avenue, Davis, 95616, California, USA

    Roy W. Qu & Damian C. Genetos

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All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and reviewed and/or edited the manuscript before submission.

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Glossary

Cre-lox recombination

A site-specific recombinase technology that is used to produce deletions, insertions, translocations and inversions at specific sites in the DNA of cells.

Anabolic loading

Mechanical loading that increases the abundance of bone.

Pannexin channels

A family of vertebrate proteins that predominantly exist as large transmembrane channels connecting the intracellular and extracellular space.

Chondron pellets

Groups of chondrocytes and their adjacent pericellular environment that have been centrifuged to form dense pellets.

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Donahue, H., Qu, R. & Genetos, D. Joint diseases: from connexins to gap junctions. Nat Rev Rheumatol 14, 42–51 (2018). https://doi.org/10.1038/nrrheum.2017.204

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