The EphA4 Signaling is Anti-catabolic in Synoviocytes but Pro-anabolic in Articular Chondrocytes
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ORIGINAL RESEARCH
The EphA4 Signaling is Anti‑catabolic in Synoviocytes but Pro‑anabolic in Articular Chondrocytes Virginia M. Stiffel1 · Alexander Thomas1,2 · Charles H. Rundle1,2 · Matilda H.‑C. Sheng1,2 · Kin‑Hing William Lau1,2 Received: 2 April 2020 / Accepted: 6 August 2020 © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020
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 proteoglycanproducing 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. Keywords EphA4 · Articular cartilage · Chondrocytes · Synovial membrane · Synoviocytes · Rho GTPases
Introduction Erythropoietin-producing human hepatocellular (Eph) receptors belong to the largest receptor protein-tyrosine kinases family. There are two subfamilies of Eph receptors: EphAs (A1-A8 and A10) and EphBs (B1-B4 and B6). Eph receptors are activated by membrane-bound ligands, ephrins (Efns), located on the cell surface of neighboring cells [1]. There are also two structurally distinct subfamilies of Efn ligands: EfnA (A1-A5) and EfnB (B1-B5). Eph receptors of * Kin‑Hing William Lau [email protected] 1
Musculoskeletal Disease Center (151), Jerry L. Pettis Memorial V.A. Medical Center, 11201 Benton Street, Loma Linda, CA 92357, USA
Department of Medicine, Loma Linda Unive
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