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The EphA4 Signaling is Anti-catabolic in Synoviocytes but Pro-anabolic in Articular Chondrocytes

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Abstract

The expression and activation of EphA4 in the various cell types in a knee joint was upregulated upon an intraarticular injury. To determine if EphA4 signaling plays a role in osteoarthritis, we determined whether deficient EphA4 expression (in EphA4 knockout mice) or upregulation of the EphA4 signaling (with the EfnA4-fc treatment) would alter cellular functions of synoviocytes and articular chondrocytes. In synoviocytes, deficient EphA4 expression enhanced, whereas activation of the EphA4 signaling reduced, expression and secretion of key inflammatory cytokines and matrix metalloproteases. Conversely, in articular chondrocytes, activation of the EphA4 signaling upregulated, while deficient EphA4 expression reduced, expression levels of chondrogenic genes (e.g., aggrecan, lubricin, type-2 collagen, and Sox9). EfnA4-fc treatment in wildtype, but not EphA4-deficient, articular chondrocytes promoted the formation and activity of acidic proteoglycan-producing colonies. Activation of the EphA4 signaling in articular chondrocytes upregulated Rac1/2 and downregulated RhoA via enhancing Vav1 and reducing Ephexin1 activation, respectively. However, activation of the EphA4 signaling in synoviocytes suppressed the Vav/Rac signaling while upregulated the Ephexin/Rho signaling. In summary, the EphA4 signaling in synoviocytes is largely of anti-catabolic nature through suppression of the expression of inflammatory cytokines and matrix proteases, but in articular chondrocytes the signaling is pro-anabolic in that it promotes the biosynthesis of articular cartilage. The contrasting action of the EphA4 signaling in synoviocytes as opposing to articular chondrocytes may in part be mediated through the opposite differential effects of the EphA4 signaling on the Vav/Rac signaling and Ephexin/Rho signaling in the two skeletal cell types.

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Data Availability

All research data of this study and materials used in this study are stored in the laboratory of Dr. Kin-Hing William Lau, and they may be available to others upon request in writing and approval from the Research Office of the Loma Linda VA Healthcare system.

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Acknowledgements

The work is supported in part by a Grant from the Department of Defense, the US Army Medical Research and Materiel Command (USAMRMC) under Grant No. W81XWH-14-1-0207 and a Merit Review Grant (IO1 BX002964) from the Biomedical Laboratory Research and Development Service, Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development. The views, opinions and/or findings contained in this report are those of the authors and should not be construed as an official position, policy or decision of the US Army, the Department of Veterans Affairs, or the US Government, unless so designated by other documentation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. In conducting research using animals, the investigators adhered to the Animal Welfare Act Regulations and other Federal statutes relating to animals and experiments involving animals and the principles set forth in the current version of the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DNA Molecules. Dr. Lau is also the recipient of a Research Career Scientist Award (1K6 BX002782) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development.

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Authors and Affiliations

  1. Musculoskeletal Disease Center (151), Jerry L. Pettis Memorial V.A. Medical Center, 11201 Benton Street, Loma Linda, CA, 92357, USA

    Virginia M. Stiffel, Alexander Thomas, Charles H. Rundle, Matilda H.-C. Sheng & Kin-Hing William Lau

  2. Department of Medicine, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA

    Alexander Thomas, Charles H. Rundle, Matilda H.-C. Sheng & Kin-Hing William Lau

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  1. Virginia M. Stiffel
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Contributions

K-HWL, VS, and MS contributed to the conception and design of the study. Material preparation and data collection were performed by VS, AT, and CR. Data analyses were performed by K-HWL and VS. The first draft of the manuscript was written by K-HWL. All authors commented on previous versions of the manuscript, read and approved the final manuscript.

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Correspondence to Kin-Hing William Lau.

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All authors (Virginia Stiffel, Alexander Thomas, Charles H. Rundle, Matilda H.-C. Sheng, and Kin-Hing William Lau) have no conflict of interest to declare.

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All animal protocols were reviewed and approved by the Animal Care and Use Committee of the Pettis Memorial VA Medical Center and the Animal Care and Use Review Office (ACURO) of US Army Medical Research and Materiel Command of the Department of Defense. In conducting research using animals, the investigators adhered to the Animal Welfare Act Regulations and other Federal statutes relating to animals and experiments involving animals.

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Stiffel, V.M., Thomas, A., Rundle, C.H. et al. The EphA4 Signaling is Anti-catabolic in Synoviocytes but Pro-anabolic in Articular Chondrocytes. Calcif Tissue Int 107, 576–592 (2020). https://doi.org/10.1007/s00223-020-00747-7

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