Degboe, Y., Sunzini, F., Sood, S., Bozec, A., Sokolova, M. V., Zekovic, A., McInnes, I. B. , Schett, G. and Goodyear, C. S. (2022) Apremilast inhibits inflammatory osteoclastogenesis. Rheumatology, 61(1), pp. 452-461. (doi: 10.1093/rheumatology/keab315) (PMID:33788924)
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Abstract
Objectives: Psoriatic arthritis (PsA) is associated with bone erosion and inflammation-induced bone loss, which are mediated by osteoclasts (OC) and modulated by inflammatory cytokines. Apremilast (APR) (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 APR affects osteoclast formation in humans. Methods: Osteoclastogenic cytokine production by activated human peripheral blood mononuclear cells (PBMCs) was measured in the presence and absence of APR. Effects of APR 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 APR on ex vivo osteoclast differentiation were compared in PsA, pre-PsA and psoriasis patients, as well as in healthy controls. Results: APR significantly impaired the expression of key osteoclastogenic cytokines in activated PBMCs. Furthermore, APR 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 APR. Finally, APR inhibited expression of the key osteoclast fusion protein dendritic cell-specific transmembrane protein. Conclusion: Phosphodiesterase 4 targeting by APR not only inhibits osteoclastogenic cytokine production, but also directly suppresses inflammation-driven osteoclastogenesis. These data provide initial evidence that APR has the potential to provide a direct bone protective effect in PsA.
| Item Type: | Articles |
|---|---|
| Additional Information: | This study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) by projects FOR2886 PANDORA and CRC1181. Additional funding was received by the Bundesministerium für Bildung und Forschung (BMBF) BMBF-MASCARA and the IMI funded project EU IMI2-RTCure. Y.D., M.V.S. and A.Z. received funding from the PARTNER fellowship. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | McInnes, Professor Iain and Sood, Dr Shatakshi and Sunzini, Miss Flavia and Degboe, Yannick and Goodyear, Professor Carl |
| Authors: | Degboe, Y., Sunzini, F., Sood, S., Bozec, A., Sokolova, M. V., Zekovic, A., McInnes, I. B., Schett, G., and Goodyear, C. S. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
| Journal Name: | Rheumatology |
| Publisher: | Oxford University Press |
| ISSN: | 1462-0324 |
| ISSN (Online): | 1462-0332 |
| Published Online: | 31 March 2021 |
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