Psoriatic arthritis (PsA) is associated with bone erosion and inflammation-induced bone loss, which are mediated by osteoclasts and modulated by inflammatory cytokines. Apremilast (a selective phosphodiesterase 4 inhibitor) is efficacious in PsA and acts by inhibiting cytokine production. However, there are no direct data informing whether and how apremilast affects osteoclast formation in humans.Osteoclastogenic cytokine production by activated human peripheral blood mononuclear cells (PBMCs) was measured in the presence and absence of apremilast. Effects of apremilast on osteoclast differentiation were tested (i) in co-cultures of activated PBMCs and human CD14+ blood monocytes as well as (ii) in CD14+ blood monocytes stimulated with activated-PBMCs supernatant, TNF or IL-17A. Bone resorption was measured on OsteoAssay plates. Effects of apremilast on ex vivo osteoclast differentiation were compared in PsA, pre-PsA and psoriasis patients as well as in healthy controls.Apremilast significantly impaired the expression of key osteoclastogenic cytokines in activated PBMCs. Furthermore, apremilast dose-dependently and significantly inhibited activated PBMC-driven osteoclast differentiation, and ex-vivo osteoclast differentiation of PBMCs derived from PsA and pre-PsA patients, but not from psoriasis patients or healthy controls. TNF and IL-17A-enhanced osteoclastogenesis and osteolytic activity of CD14+ blood monocytes from PsA patients was also significantly inhibited by apremilast. Finally, apremilast inhibited expression of the key osteoclast fusion protein DC-STAMP.Phosphodiesterase-4 targeting by apremilast not only inhibits osteoclastogenic cytokine production, but also directly suppresses inflammation-driven osteoclastogenesis. These data provide initial evidence that apremilast has the potential to provide a direct bone protective effect in PsA.
Yannick Degboé, Flavia Sunzini, Shatakshi Sood, Aline Bozec, Maria V Sokolova, Ana Zekovic, Iain B McInnes, Georg Schett, Carl S Goodyear