McGowan H W, Schuijers J A, Grills B L, McDonald S J, Rickard J A, Silke J, McDonald A C
La Trobe University, Department of Human Biosciences, La Trobe University, Bundoora, Australia.
J Musculoskelet Neuronal Interact. 2014 Dec;14(4):454-63.
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.
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.
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.
Our results suggest that SHARPIN plays a significant role in skeletal homeostasis and that this role is strongly regulated through TNF pathways.
SHARPIN是线性泛素链组装复合体（LUBAC）的一个亚基，可调节核因子κB（NF-κB）的激活，NF-κB是骨骼稳态中的关键转录因子。SHARPIN基因突变（cpdm）小鼠会发生慢性增殖性皮炎和全身炎症。Cpdm小鼠具有骨质疏松表型，其特征是皮质骨和小梁骨体积减少，但这是否是高炎症表型的结果尚不清楚。cpdm小鼠的炎症表型可通过肿瘤坏死因子（Tnf）缺乏来预防，因此我们检测了cpdm.Tnf（-/-）小鼠，以研究SHARPIN在骨骼发育中的作用。
本研究通过分析对照（CTRL）、cpdm、Tnf（-/-）（TNF基因敲除，TNF KO）和cpdm.Tnf（-/-）（cpdm/TNF KO）小鼠骨骼的基因表达、显微计算机断层扫描（μCT）和生物力学特性来确定SHARPIN和TNF在骨骼中的相互作用程度。
cpdm小鼠中白细胞介素-1β（IL-1β）、TNF和半胱天冬酶-3的基因表达增加，但在cpdm/TNF KO小鼠中与对照值相当。cpdm小鼠皮质骨和小梁骨的减少转化为骨强度（极限应力和峰值力）的损失。Cpdm/TNF KO小鼠骨骼的发育与对照骨骼相似或更强。
我们的结果表明，SHARPIN在骨骼稳态中起重要作用，并且该作用通过TNF途径受到强烈调节。
