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Transcriptome analysis of the mandibles from FcgRIIB-deficient mouse model of lupus

ABSTRACT: To identify the extensive complexity of transcriptome in Fc gamma receptor IIB knockout (FcgRIIB−/−) mandibles. We performed gene expression profiling of mandibular bone from wild-type (WT) and FcgRIIB−/− mice at 6 months of age. Our study reports the first transcriptomic analysis in mandibles of FcgRIIB-deficient mice using RNA-sequencing (RNA-seq). The data were validated by qPCR analysis. qPCR analysis revealed similar results compared to RNA-seq data. This finding disclosed the relevant differentially expressed genes (DEGs) and clarify the mechanism underlying the pathogenesis of osteopenia. We provide novel candidate genes and enriched pathways that contribute to mandibular bone loss in FcgRIIB−/− mice during lupus development. Sufu and Serpina12 were identified as candidate molecular targets regulating osteoclastogenesis and osteogenesis, respectively.

ORGANISM(S): Mus musculus

PROVIDER: GSE179155 | GEO | 2021/09/29

REPOSITORIES: GEO

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Project description:Background Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. Materials and Methods To determine whether Dspp+/- mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/-, and Dspp homozygous (Dspp-/-) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/- mice over time, condyles of Dspp+/- and WT mice were analyzed radiologically, histologically, and immunohistochemically. Results Micro-CT and histomorphometric analyses revealed that Dspp+/- and Dspp-/- mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp-/- mice which exhibited tooth loss, Dspp+/- mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/- mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/- mice showed increased distribution of osteoclast in the subchondal bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. Conclusions Dspp+/- mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

Project description:Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing the autoimmune disease systemic lupus erythematosus. However, the biological role of IRF5 in lupus pathogenesis, if any, is not known. In this study we show that IRF5 is absolutely required for disease development in the FcgRIIB-/-Yaa and FcgRIIB-/- lupus models. In contrast to IRF5-sufficient FcgRIIB-/-Yaa mice, IRF5-deficient FcgRIIB-/-Yaa mice do not develop lupus manifestations and have a phenotype comparable to wildtype mice. Strikingly, full expression of IRF5 is required for the development of autoimmunity, as IRF5-heterozygotes had dramatically reduced disease. One effect of IRF5 is to induce the production of the type I interferon IFN-gamma, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcgRIIB-/-Yaa mice lacking the type I interferon receptor IFNAR1. Unlike the IRF5-deficient and IRF5-heterozygous FcgRIIB-/-Yaa mice, IFNAR1-deficient FcgRIIB-/-Yaa mice maintained a substantial level of residual disease. Furthermore, in FcgRIIB-/- mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations, indicating that the beneficial effects of IRF5 deficiency in FcgRIIB-/-Yaa mice are not due only to inhibition of the enhanced TLR7 signaling associated with the Yaa mutation. Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I interferon production. The fact that even IRF5 heterozygous mice developed minimal disease makes IRF5 a particularly attractive therapeutic target. Serum samples from a total of 70 mice were run on the Utz Lab Whole Protein Autoantigen Array V1.0 (a single-color platform) in order to profile their autoantibodies against a library of autoimmune antigens. All samples were run once with no replicates. The samples consisted of the following groups: For data appearing in Figure 3D, illustrating that mice lacking IRF5 have their autoantibody levels significantly affected: R2Yaa IRF5+/+: 12 R2Yaa IRF5+/-: 11 R2Yaa IRF5-/-: 14 C57BL/6 ("WT" control): 13 Total mice (arrays) for this group: 50 For data appearing in Figure 6D, illustrating that mice lacking Ifnar1 do not have their autoantibody levels significantly affected: R2Yaa Ifnar+/+: 10 R2Yaa Ifnar-/-: 10 Total mice (arrays) for this group: 20

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Transcriptome analysis of the mandibles from FcgRIIB-deficient mouse model of lupus

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