Anti-inflammatory, but not osteoprotective, effect of the TRAF6/CD40 inhibitor 6877002 in rodent models of local and systemic osteolysis
Marino S, Hannemann N, Bishop RT, Zeng F, Carrasco G, Meurisse S, Li B, Sophocleous A, Sparatore A, Bäuerle T, Vukicevic S, Auberval M, Mollat P, Bozec A, Idris AI (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 195
Article Number: 114869
DOI: 10.1016/j.bcp.2021.114869
Abstract
NFκB plays a key role in inflammation and skeletal disorders. Previously, we reported that pharmacological inhibition of NFκB at the level of TRAF6 suppressed RANKL, CD40L and IL1β-induced osteoclastogenesis and attenuated cancer-induced bone disease. TNFα is also known to regulate TRAF6/NFκB signalling, however the anti-inflammatory and osteoprotective effects associated with inhibition of the TNFα/TRAF6/NFκB axis have not been investigated. Here, we show that in vitro and ex vivo exposure to the verified small-molecule inhibitor of TRAF6, 6877002 prevented TNFα-induced NFκB activation, osteoclastogenesis and calvarial osteolysis, but it had no effects on TNFα-induced apoptosis or growth inhibition in osteoblasts. Additionally, 6877002 disrupted T-cells support for osteoclast formation and synoviocyte motility, without affecting the viability of osteoblasts in the presence of T-cells derived factors. Using the collagen-induced arthritis model, we show that oral and intraperitoneal administration of 6877002 in mice reduced joint inflammation and arthritis score. Unexpectedly, no difference in trabecular and cortical bone parameters were detected between vehicle and 6877002 treated mice, indicating lack of osteoprotection by 6877002 in the arthritis model described. Using two independent rodent models of osteolysis, we confirmed that 6877002 had no effect on trabecular and cortical bone loss in both osteoporotic rats or RANKL- treated mice. In contrast, the classic anti-osteolytic alendronate offered complete osteoprotection in RANKL- treated mice. In conclusion, TRAF6 inhibitors may be of value in the management of the inflammatory component of bone disorders, but may not offer protection against local or systemic bone loss, unless combined with anti-resorptive therapy such as bisphosphonates.
Authors with CRIS profile
Nicole Hannemann
Medizinische Fakultät
Tobias Bäuerle
Professur für Multimodale Bildgebung in der präklinischen Forschung
Aline Bozec
Professur für Experimentelle Immuntherapie
Involved external institutions
University of Sheffield
United Kingdom (GB)
University of Zagreb / Sveučilište u Zagrebu
Croatia (HR)
Galapagos SASU
France (FR)
Università degli studi di Milano
Italy (IT)
European University Cyprus (EUC) / Ευρωπαϊκό Πανεπιστήμιο Κύπρου
Cyprus (CY)
United Kingdom (GB)
University of Zagreb / Sveučilište u Zagrebu
Croatia (HR)
Galapagos SASU
France (FR)
Università degli studi di Milano
Italy (IT)
European University Cyprus (EUC) / Ευρωπαϊκό Πανεπιστήμιο Κύπρου
Cyprus (CY)
How to cite
APA:
Marino, S., Hannemann, N., Bishop, R.T., Zeng, F., Carrasco, G., Meurisse, S.,... Idris, A.I. (2022). Anti-inflammatory, but not osteoprotective, effect of the TRAF6/CD40 inhibitor 6877002 in rodent models of local and systemic osteolysis. Biochemical Pharmacology, 195. https://dx.doi.org/10.1016/j.bcp.2021.114869
MLA:
Marino, Silvia, et al. "Anti-inflammatory, but not osteoprotective, effect of the TRAF6/CD40 inhibitor 6877002 in rodent models of local and systemic osteolysis." Biochemical Pharmacology 195 (2022).
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