Dual neutralisation of IL-17F and IL-17A with bimekizumab blocks inflammation-driven osteogenic differentiation of human periosteal cells

Abstract

ObjectivesInterleukin (IL)-17 signalling has been shown to be a key regulator of disease in ankylosing spondylitis (AS) with several IL-17 blockers currently clinically approved. Despite this, the role of IL-17 in bone pathology is poorly understood. This study aimed to investigate IL-17 signalling in the context of pathological bone formation.MethodsA biomimetic human periosteum-derived cell (hPDC) model of osteogenic differentiation was used in combination with recombinant IL-17 cytokines, T-cell supernatants or serum from patients with AS. IL-17A, IL-17F and bimekizumab monoclonal antibodies were used to block IL-17 cytokine action.ResultsRecombinant IL-17A and IL-17F are pro-osteogenic with respect to hPDC differentiation. T helper 17 or γδ-T cell supernatants also potently stimulated in vitro bone formation, which was blocked deeper by dual inhibition of IL-17A and IL-17F than by neutralisation of IL-17A or IL-17F individually. Osteogenic blockade may be due to an increase in expression of the Wnt antagonist DKK1. Interestingly, osteocommitment was also induced by serum obtained from patients with AS, which was also abrogated by dual neutralisation of IL-17A and IL-17F.ConclusionsThese data show for the first time that IL-17A and IL-17F enhance in vitro osteogenic differentiation and bone formation from hPDCs, inhibition of which may offer an attractive therapeutic strategy to prevent pathological bone formation.

An Overview of Bimekizumab for the Treatment of Psoriatic Arthritis: The Evidence so Far

“…In enthesitis, a central pathologic process in PsA, Tγδ cells have recently been described that are capable of producing both IL-17A and IL-17F even independently of IL-23 stimulation. 17 IL-17A and F had already been shown to promote osteogenic differentiation in in vitro models of human periosteum activated through the use of Th17 and Tγδ cells or through culture with serum from patients with ankylosing spondylitis, 18 a mechanism potentially implied in the development of enthesitis. Importantly, both cytokines seem to be equipotent in this role, unlike in inflammatory processes where IL-17F seems to be less potent.…”

“…Importantly, both cytokines seem to be equipotent in this role, unlike in inflammatory processes where IL-17F seems to be less potent. 18 …”

“… 9 , 19 In in vitro models of human periosteum dual blockade of IL-17A and F was also more effective in suppressing osteogenic differentiation than the blockade of either cytokine individually. 18 …”

“…Interestingly, in Tγδ cells, the predominant IL-17 production seems to be the F subtype. 18 Also of note is the recent description that the IL-17receptorC (IL-17RC) competes with IL-17RA for IL-17F, IL-17A and IL-17A/F heterodimers, 22 suggesting the possibility of IL-17RA-independent signaling pathways (and thus not targeted by brodalumab, an anti-IL17RA monoclonal antibody).…”

IL-17A and TNF Modulate Normal Human Spinal Entheseal Bone and Soft Tissue Mesenchymal Stem Cell Osteogenesis, Adipogenesis, and Stromal Function

“…IL-17A (50 ng/mL) and TNF (1 ng/mL) (both from PeproTech, Rocky Hill, NJ, USA) were employed for all differentiations in this study. These were used in concentrations similar to previous works looking at cytokine influences on osteogenesis in MSCs [26][27][28]. However, it is recognized that in vivo cytokine concentrations are much lower, usually in the pg/mL range [12,29], and the effects are mimicked using the concentrations employed in this and other studies.…”