FRI0365 PDE4 TARGETING SELECTIVELY INHIBITS INFLAMMATORY-DRIVEN OSTEOCLASTOGENESIS
Authors: Yannick Degboe, Iain Mcinnes, Carl Goodyear
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Patients suffering from Psoriatic arthritis (PsA) commonly develop bone erosions and inflammatory-induced bone loss. This process is mediated by osteoclasts derived from monocytic precursors, and modulated by inflammatory cytokines (i.e. TNF, IL-1, IL-6, IL-17, IL-10 and GM-CSF) from immune and stromal cells. In immune cells (including CD14<sup>+</sup> osteoclast pre-cursors), PDE4, an enzyme responsible for hydrolysing cyclic AMP to inactive AMP, drives inflammatory effects [1]. Importantly, Apremilast (APR; a selective PDE4 inhibitor) has known efficacy in PsA [2], and decreases pro-inflammatory mediators whilst increasing anti-inflammatory mediators (IL-10) [3]. Although published data indirectly suggest a positive impact of APR on bone in PsA, data is lacking with regard to the impact on bone resorption. <h3>Objectives</h3> To evaluate the impact of a selective inhibition of PDE4 by APR on osteoclastogenesis from human CD14<sup>+</sup> precursors. <h3>Methods</h3> Osteoclasts were differentiated from primary human CD14<sup>+</sup> blood monocytes (healthy controls) with RANKL and MCSF, in the presence or absence of APR. To specifically study the impact of APR on osteoclastogenesis in an inflammatory context, osteoclastogenesis was also undertaken in the presence of: <b><i>(i)</i></b> TNF, <b><i>(ii)</i></b> Supernatants from activated Peripheral Blood Mononuclear Cells (PBMC) or activated CD3 cells, treated with or without APR, <b><i>(iii)</i></b> Co-culture with activated PBMC or activated CD3 cells, treated with or without APR. TRAP<sup>+</sup> multinucleated cells (mature osteoclasts) were enumerated via microscopy. <h3>Results</h3> In a non-inflammatory context, PDE4 inhibition by APR did not affect the differentiation of CD14<sup>+</sup> precursors into mature osteoclasts. However, TNF-enhanced osteoclastogenesis was significantly decreased by APR (-30.0% +/- 14.9; p=0.0279).The treatment of either activated PBMCs or purified CD3<sup>+</sup> T cells with APR substantially reduced cellular activation. In PBMCs this decrease in cellular activation resulted in a decrease in conditioned media-driven osteoclastogenesis (-49.7% +/- 13.2; p=0.0385). In comparison, APR treatment of purified CD3<sup>+</sup> T cells did not reduce their osteoclastogenic potential. <h3>Conclusion</h3> The results of this study reveal that PDE4 targeting potently inhibits inflammatory-driven osteoclastogenesis. Moreover, these data also suggest that CD3<sup>+</sup> T cells are not the main target of PDE4 inhibition in this context. In summation, our study supports the hypothesis that APR can modulate bone integrity in inflammatory condition such as PsA. <h3>References</h3> [1] Houslay. Drug Discov Today. 2005Nov15;10(22):1503-19. [2] Edwards. Ann Rheum Dis. 2016Jun;75(6):1065-73. Doi: 10.1136/annrheumdis-2015-207963. [3] Schafer. J Immunol Res. 2015;2015:906349. Doi: 10.1155/2015/906349. <h3>Acknowledgement</h3> YD received a fellowship from the Société Française de Rhumatologie <h3>Disclosure of Interests</h3> Yannick Degboe Grant/research support from: Celgene PARTNER Fellowship, Iain McInnes Grant/research support from: AstraZeneca, Celgene, Compugen, Novartis, Roche, UCB Pharma, Consultant for: AbbVie, Celgene, Galvani, Lilly, Novartis, Pfizer, UCB Pharma, Carl Goodyear Grant/research support from: AstraZeneca, BMS, Celgene, Janssen, MedAnnex, Pfizer and UCB, Speakers bureau: Abbvie