Adenosine A2A receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis

Aránzazu Mediero, Tuere Wilder, Lopa Shah, Bruce N. Cronstein
  • The FASEB Journal, February 2018, Federation of American Societies For Experimental Biology (FASEB)
  • DOI: 10.1096/fj.201700217r

What is it about?

Communication between osteoclasts and osteoblasts is regulated by a variety of molecules. Among them we can find the axonal guidance proteins semaphorin 4D (Sema4D) and Sema3A, and adenosine, that by activation of the adenosine A2A receptors (A2AR) regulates both osteoclast and osteoblast function. In this work we asked whether A2AR regulates both osteoclast and osteoblast expression of semaphorins. To answer the question we analysed protein expression of Sema4D and Sema3A and theire receptors in an in vivo murine model of wear particle-induced osteolysis. Osteoclast/osteoblast differentiation were studied in vitro as the number of TRAP+/Alizarin Red+ cells, after challenge with CGS21680 (A2AR agonist), ZM241385 (A2AR antagonist) with/without Sema4D/Sema3A. Sema3A/PlexinA1/Neuropilin-1, Sema4D/PlexinB1, RANKL/OPG expression were studied. β-catenin activation and cytoskeleton changes were studied. In mice with wear particles implanted over the calvaria CGS21680 treatment increased bone formation in vivo, reduced Sema4D and increased Sema3A expression in comparison with mice with wear particle-induced osteolysis treated with vehicle alone. During osteoclast differentiation CGS21680 abrogated RANKL-induced Sema4D mRNA expression. PlexinA1, but not Neuropilin-1, mRNA was enhanced by CGS21680 treatment. CGS21680 enhanced Sema3A mRNA expression during osteoblast differentiation; PlexinB1 mRNA was increased 2-fold during osteoblast differentiation and was not altered by CGS21680. CGS21680 decreased RANKL, increased OPG and increased total/nuclear β-catenin expression in osteoblasts. Sema4D increased RhoA phosphorylation and FAK activation in osteoclast precursors and CGS21680 abrogated these effects. In conclusion, A2AR activation diminishes secretion of Sema4D by osteoclasts, inhibits Sema4D-mediated osteoclast activation and enhances secretion of Sema3A by osteoblasts increasing osteoblast differentiation and diminishing inflammatory osteolysis.

The following have contributed to this page: Bruce N Cronstein