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Lupus-like Disease in Fc?RIIB^-/- Mice Induces Osteopenia.

ABSTRACT: Osteoporotic fracture is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). Mice lacking Fc gamma receptor IIb (Fc?RIIB) spontaneously develop lupus-like disease or SLE at 6-month-old. The aim of this study was to investigate whether Fc?RIIB deletion induces osteopenia. ?CT analysis indicated that deleting Fc?RIIB did not affect cancellous bone microarchitecture in 3-month-old mice in which SLE had not yet developed. However, 6- and 10-month-old Fc?RIIB^-/- males that developed an SLE-like phenotype were osteopenic and Fc?RIIB deletion resulted in decreased cancellous bone volume. Histomorphometry confirmed a significant decrease in cancellous bone volume in 6- and 10-month-old Fc?RIIB^-/- males. The osteoclast number was increased without any change in osteoblast number. In vitro assays indicated that deleting Fc?RIIB increased osteoclast differentiation while alkaline phosphatase activity and mineralization were unaltered. These changes were associated with increases in steady-state mRNA levels for the osteoclast marker genes Trap and Ctsk. Moreover, Fc?RIIB^-/- mice had higher level of serum TNF?, a proinflammatory cytokine. A soluble TNF? receptor, etanercept, prevented cancellous bone loss in Fc?RIIB^-/- mice. Our results indicate that Fc?RIIB indirectly regulates cancellous bone homeostasis following SLE development. Fc?RIIB deletion induces inflammatory bone loss due to increased TNF?-mediated bone resorption without any change in bone formation in mice with SLE-like syndrome.

SUBMITTER: Visitchanakun P

PROVIDER: S-EPMC6874658 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Lupus-like Disease in FcγRIIB<sup>-/-</sup> Mice Induces Osteopenia.

Visitchanakun Peerapat P Saiworn Worasit W Jongwattanapisan Prapaporn P Leelahavanichkul Asada A Pisitkun Prapaporn P Lotinun Sutada S

Scientific reports 20191122 1

Osteoporotic fracture is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). Mice lacking Fc gamma receptor IIb (FcγRIIB) spontaneously develop lupus-like disease or SLE at 6-month-old. The aim of this study was to investigate whether FcγRIIB deletion induces osteopenia. μCT analysis indicated that deleting FcγRIIB did not affect cancellous bone microarchitecture in 3-month-old mice in which SLE had not yet developed. However, 6- and 10-month-old FcγRIIB<sup>-/-</sup> ...[more]

PMID: 31758072

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Project description:BackgroundBortezomib (Bz) is a proteasome inhibitor that directly targets antibody-producing plasma cells. We recently reported the first randomized control trial that evaluated the effects of Bz in patients with systemic lupus erythematosus (SLE). In that study, we demonstrated that Bz treatment is associated with many adverse reactions in patients with refractory disease. In the present study, we examine the therapeutic and toxic effects of Bz on MRL/MpJ-lpr/lpr (MRL/lpr) mice with severe disease activity.MethodsFemale MRL/lpr mice at 10 and 14 weeks of age were treated with phosphate buffered saline (PBS) (n = 19), Bz (750 μg/kg twice weekly) (n = 27), or cyclophosphamide (Cyc) (1 mg/body, once in 2 weeks) (n = 20). Cellular subsets, serum immunoglobulin, anti-double-stranded DNA (anti-dsDNA) antibody titer, and a pathological index of glomerulonephritis were then analyzed at 22 weeks of age. Survival curves of the 10-week-old and 14-week-old Bz-treated groups were compared. Blood counts, creatinine, liver enzymes, and serum cytokine levels were measured 1 week after Bz treatment. Gene expression profiling of spleens from Bz and Cyc treatment mice were compared with those from control mice.ResultsThe anti-dsDNA antibody levels were significantly higher in 14-week-old than in 10-week-old mice, indicating a higher disease activity at 14 weeks. A significant decrease in the number of splenic cells and glomerulonephritis index was observed in Bz-treated and Cyc-treated mice. Bz, but not Cyc, significantly decreased serum immunoglobulin and anti-dsDNA antibody titer levels. Survival curve analysis revealed a significantly higher mortality rate in 14-week-old than in 10-week-old Bz-treated and control groups. Following two injections of Bz, serum IL-6 and TNF-α levels were significantly more elevated in 14-week-old than in 10-week-old mice. Potentially immunogenic molecules, such as heat shock proteins, were characteristically upregulated in spleens of Bz-treated but not Cyc-treated mice.ConclusionsIn spite of its therapeutic effect, Bz treatment had more toxic effects associated with increased proinflammatory cytokine levels in mice with a higher disease activity. Understanding the mechanism of the toxicity and developing preventive strategies against it is important for the safe clinical application of Bz in human SLE.

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Lupus-like Disease in Fc?RIIB^-/- Mice Induces Osteopenia.

Publications

Lupus-like Disease in FcγRIIB<sup>-/-</sup> Mice Induces Osteopenia.

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Dataset Information

Lupus-like Disease in Fc?RIIB-/- Mice Induces Osteopenia.

Publications

Lupus-like Disease in FcγRIIB<sup>-/-</sup> Mice Induces Osteopenia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Lupus-like Disease in Fc?RIIB^-/- Mice Induces Osteopenia.