Background/Purpose: PsA is associated with bone erosion and inflammation-induced bone loss. This process is mediated by osteoclasts, and modulated by inflammatory cytokines (i.e. TNF, IL-1, IL-6, IL-17, and GM-CSF) from immune and stromal cells. Apremilast (APR; a selective phosphodiesterase 4 inhibitor) has known efficacy in PsA, and decreases pro-inflammatory mediators. Although published data indirectly suggest a positive impact of APR on inflammatory-driven bone loss in PsA, data is lacking with regard to the impact on osteoclast generation and activity.

Methods: Osteoclasts were differentiated from primary human CD14⁺ blood monocytes (derived from PsA patients and healthy controls (HC)) with M-CSF, sub-optimal level of RANKL, plus additional inflammatory-associated stimuli. In brief, osteoclastogenesis was undertaken in the presence of: (i) TNF, (ii) Supernatants from activated Peripheral Blood Mononuclear Cells (PBMC) treated with or without APR, (iii) Co-culture with activated PBMC, pre-treated with or without APR. Mature osteoclasts were enumerated (Tartrate-Resistant Acid Phosphatase staining/microscopy) and assessed for resorptive activity (Osteo Assay Surface/microscopy). The direct impact of APR on lymphocytes proliferation and activation was also assessed via flow cytometry and cytokines assay.

Results: APR significantly decreased TNF-enhanced osteoclastogenesis and osteolytic activity in both PsA and HC samples (Figure 1). Notably, APR had a dramatic impact on the ability of monocytic precursors to respond to osteoclastogenic signals, but was also able to substantially modulate the capacity of pre-osteoclast to respond to the same signals.

The treatment of activated PBMCs with APR markedly reduced lymphocytes proliferation (CD4, CD8, B cells), and activation (CD25 membrane expression; TNF, IL-17A, M-CSF, IL-2 production in supernatants) (Figure 2). This modulation resulted in a decrease in the capacity of either PBMC condition media or PBMC coculture-driven osteoclastogenesis.

Conclusion: Phosphodiesterase 4 targeting by APR inhibits in vitro inflammation-driven osteoclastogenesis. Our study supports the hypothesis that this therapeutic approach can modulate bone integrity in inflammatory condition such as PsA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/apremilast-inhibits-immune-cells-support-of-inflammatory-osteoclastogenesis/