Abstract
Patients with systemic lupus erythematosus (SLE) have increased inflammatory cytokines, leading to periodontitis and alveolar bone loss. However, the mechanisms driving this phenomenon are still unknown. Here, we have identified novel therapeutic targets for and mediators of lupus-mediated bone loss using RNA-sequencing (RNA-seq) in a FcγRIIB-/- mouse model of lupus associated osteopenia. A total of 2,710 upregulated and 3,252 downregulated DEGs were identified. The GO and KEGG annotations revealed that osteoclast differentiation, bone mineralization, ossification, and myeloid cell development were downregulated. WikiPathways indicated that Hedgehog, TNFα NF-κB and Notch signaling pathway were also decreased. We identified downregulated targets, Sufu and Serpina12, that have important roles in bone homeostasis. Sufu and Serpina12 were related to Hedgehog signaling proteins, including Gli1, Gli2, Gli3, Ptch1, and Ptch2. Gene knockdown analysis demonstrated that Sufu, and Serpina12 contributed to osteoclastogenesis and osteoblastogenesis, respectively. Osteoclast and osteoblast marker genes were significantly decreased in Sufu-deficient and Serpina12-deficient cells, respectively. Our results suggest that alterations in Hedgehog signaling play an important role in the pathogenesis of osteopenia in FcγRIIB-/- mice. The novel DEGs and pathways identified in this study provide new insight into the underlying mechanisms of mandibular bone loss during lupus development.
Highlights
Patients with systemic lupus erythematosus (SLE) have increased inflammatory cytokines, leading to periodontitis and alveolar bone loss
In line with our expectations[16], cancellous bone volume, trabecular thickness, and bone mineral density (BMD) were significantly decreased in the mandibles of FcγRIIB-/- mice compared to WT controls (Fig. 1a,b)
Knockdown of Serpina[12] decreased Dmp and Ibsp expression in WT osteoblasts. These findings indicated that suppressor of fused (Sufu) plays important role in osteoclast differentiation and that Serpina[12] is a key regulator of osteoblastogenesis that may contribute to the skeletal phenotype occurring in lupus
Summary
Patients with systemic lupus erythematosus (SLE) have increased inflammatory cytokines, leading to periodontitis and alveolar bone loss. Patients with chronic periodontitis have high level of RANKL which is correlated with increased number of Gram-negative bacteria, such as Porphyromonas gingivalis in periodontal tissue[1] This organism has virulence factors that induce inflammatory responses, eventually leading to alveolar bone loss. Chronic inflammatory diseases such as diabetes, rheumatoid arthritis, and systemic lupus erythematosus (SLE) are associated with an increased risk of periodontal disease. The stimulation of ITIM-containing FcγRIIB and B cell receptor recruits phosphatases including SH2 domain containing inositol polyphosphate 5’ phosphatase (SHIP) and SH2 domain containing protein tyrosine phosphatase 1 (SHIP1). TNFα can augment osteoclastic bone resorption via its ability to enhance RANKL-driven osteoclast differentiation
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