Session Type: Abstract Submissions (ACR)
Background/Purpose A variety of molecules mediate communication between osteoclasts and osteoblasts during bone remodeling. Netrin1 is a member of the family of axonal guidance proteins, that regulates inflammation and macrophage function. Because osteoclasts are derived from myeloid precursors we asked whether osteoclasts expressed Netrin-1 and whether A2AR activation, which diminishes osteoclast differentiation, might regulate Netrin-1 expression and inflammatory osteolysis.
Methods 1cm midline sagittal incision was made over the calvaria in C57Bl/6 mice age 6-8 weeks. Mice received no particles (Control) or 3mg of UHMWPE with 20µl of saline 0.9% or CGS21680 (A2AR agonist, 1µM, n=4 each) at the surgical site every day up to 14 days. After sacrifice, calvaria were prepared for immunostaining for Netrin1/Unc5b/DCC. Protein and mRNA expression were studied by RT-PCR and WB in mouse and human primary bone marrow-derived OC and OB in the presence/absence of CGS21680 and ZM241385 (A2AR antagonist) 1µM each.
Results UHMWPE increased expression of Netrin1 and Unc5b, but not DCC, in periosteal inflammatory infiltrates which was reversed by the A2AR agonist CGS21680. RANKL induced 25±4 and 3±0.5 fold change, respectively, in Netrin1 and Unc5b mRNA during osteoclast differentiation, changes that were completely blocked by CGS21680 (1.17±0.1, p<0.001, n=4). In contrast, DCC mRNA expression did not significantly change during osteoclast differentiation and DCC expression was unaffected by CGS21680 (1.16±0.2 fold increase vs 1.9±0.2 for RANKL, p=ns, n=4). There was no change in Netrin1 or Unc5b expression during OB differentiation. Similar changes were observed in protein expression and secretion.
Conclusion UHMWPE-induced osteolysis is regulated by Netrin1 activation. Adenosine A2AR stimulation normalizes Netrin1expression and inhibits bony destruction at sites of UHMWPE-induced osteolysis. These results suggest that targeting Netrin1 directly or via stimulation of adenosine A2AR may be a novel approach to preventing osteolysis and joint prosthesis loosening.
B. N. Cronstein,
NYU School of Medicine,
Eli Lilly and Company,
Rheumatology Reseach Foundation,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/stimulation-of-the-adenosine-a2a-receptor-a2ar-regulates-the-expression-of-netrin1-and-their-receptors-unc5b-dcc-and-inhibits-osteoclast-differentiation-and-inflammatory-bone-destruction/