OBJECTIVES: SHARPIN is a subunit of LUBAC and regulates activation of NF-κB, a pivotal transcription factor in skeletal homeostasis. Mutated SHARPIN gene (cpdm) mice develop chronic proliferative dermatitis and systemic inflammation. Cpdm mice have an osteopaenic phenotype characterised by decreased cortical and trabecular bone volume, but whether this is a consequence of the hyper-inflammatory phenotype is unknown. The inflammatory phenotype of cpdm mice is prevented by Tnf deficiency so we examined cpdm.Tnf (-/-) mice to examine the role of SHARPIN in skeletal development. METHODS: This research determined the extent to which SHARPIN and TNF interact within the skeleton through analyses of gene expression, μCT and biomechanical properties of bones of control (CTRL), cpdm, Tnf (-/-) (TNF KO) and cpdm.Tnf (-/-) (cpdm/TNF KO) mice. RESULTS: Gene expression of IL-1β, TNF and caspase-3 increased in cpdm mice but was comparable to control values in cpdm/TNF KO mice. Decreased cortical and trabecular bone in cpdm mice translated to a loss in bone strength (ultimate stress and peak force). Cpdm/TNF KO mice developed bones similar to, or stronger than, control bones. CONCLUSIONS: Our results suggest that SHARPIN plays a significant role in skeletal homeostasis and that this role is strongly regulated through TNF pathways.