Elucidation of the mechanisms of chemo-resistance and implementation of strategies to overcome it will be pivotal to improve the survival for osteosarcoma (OS) patients. We here suggest that sphingosine kinase-1 (SphK1) might be the key factor contributing to chemo-resistance in OS. Our Western-blots and immunohistochemistry results showed that SphK1 is over-expressed in multiple clinical OS tissues. Over-expression of SphK1 in OS cell line U2OS promoted its growth and endorsed its resistance against doxorubicin, while knocking-down of SphK1 by shRNA inhibited U2OS cell growth and increased its sensitivity to doxorubicin. Co-administration phenoxodiol with doxorubicin synergistically inhibited SphK1 activity to trigger cellular ceramide accumulation, and achieved synergistic anti-OS growth effect, accompanied with a significant increased of apoptosis and cytotoxicity. Increased cellular level of ceramide by the co-administration induced the association between Akt and Protein Phosphatase 1 (PP1) to dephosphorylate Akt, and to introduce a constitutively active Akt (CA-Akt) restored Akt activation and diminished cell growth inhibition. Further, phenoxodiol and doxorubicin synergistically activated apoptosis signal-regulating kinase 1(ASK1)/c-jun-NH2-kinase (JNK) signaling, which also contributed to cell growth inhibition. Significantly, the role of SphK1 in OS cell growth and the synergistic anti-OS effect of phenoxodiol and doxorubicin were also seen in a mice OS xenograft model. In conclusion, our data suggest that SphK1 might be a critical oncogene of OS and co-administration phenoxodiol with doxorubicin synergistically inhibited the activity of SphK1 to suppress osteosarcoma cell growth both in vivo and in vitro.

Objectives. Bone destruction is a remarkable feature of inflammatory arthritis. It remains unknown why arthritis associated with the systemic autoimmune/inflammatory condition systemic lupus erythematosus (SLE) does not result in erosion and destruction. We aimed to determine the role of autoantibody in the pathogenesis of non-erosive arthritis in SLE. Methods. We analysed medical record of SLE patients, investigated whether autoantibody induces arthritis lacking bone destruction in animal models and determined whether SLE autoantibody inhibits osteoclastogenesis induced by RANKL in vitro experiments. Results. We found that arthritis lacking bone erosions is common in SLE patients and lupus-prone mice. Intraarticular injection of lupus serum or IgG induces immune complex deposition and arthritis, but does not result in bone destruction. Deposition of IgG, monocytes/macrophages and TNF-a is all required for the development of arthritis. Lupus serum or IgG inhibits RANKLinduced differentiation of monocytes into osteoclast in a dosedependent manner. FccR acts as co-receptors for RANKL and is involved in osteoclastogenesis. Deficiency of FccRII or FccRIII does not affect osteoclastogenesis in the presence of SLE IgG. However, lupus IgG competes for FccRI binding with RANKL, thereby reducing osteoclastogenesis. Conclusion. Observations from this study demonstrate that IgG from SLE patients can induce arthritis and inhibits RANKL-induced osteoclastogenesis through competitive occupation of FccRI on monocytes/macrophages. This study improves the understanding of the pathophysiology of SLEassociated arthritis and offers a protective mechanism (FccRI inhibition) that may be targeted in other forms of autoimmune/ inflammatory arthritis, such as RA, to prevent or limit bone erosion and inflammatory bone loss.

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The onset of hepatic disorders in patients with systemic lupus erythematosus (SLE) is frequent; however, the etiology and liver pathogenesis of SLE remain unknown. In the present study, the role of hepatic deposited immunoglobulin G (IgG) in SLE-derived liver damage was investigated. From a retrospective analysis of the medical records of 404 patients with lupus and from experimental studies on mice models, we found that liver dysfunction is common in SLE and liver damage with IgG deposition spontaneously develops in lupus-prone mice. Liver injury was recreated in mice by injecting IgG from lupus serum intrahepatically. The inflammation intensity in the liver decreased with IgG depletion and the lupus IgG-induced liver inflammation in FcγRIII-deficient mice was comparatively low; while, inflammation was increased in FcγRIIb-deficient mice. Macrophages, Kupffer cells, natural killer cells, and their products, but not lymphocytes, are required for the initiation of SLE-associated liver inflammation. Blocking IgG signaling using a spleen tyrosine kinase (Syk) inhibitor suppressed the liver damage. Our findings provided evidence of spontaneously established liver damage in SLE. They also suggested that hepatic-deposited lupus IgG is an important pathological factor in the development of liver injury and that hepatic inflammation is regulated by the Syk signaling pathway. Thus, Syk inhibition might promote the development of a therapeutic strategy to control liver damage in patients with SLE.