SH3BP2 Gain-Of-Function Mutation Exacerbates Inflammation and Bone Loss in a Murine Collagen-Induced Arthritis Model

Mukai, Tomoyuki; Gallant, Richard; Ishida, Shohei; Yoshitaka, Teruhito; Kittaka, Mizuho; Nishida, Keiichiro; Fox, David A.; Morita, Yoshitaka; Ueki, Yasuyoshi

doi:10.1371/journal.pone.0105518

Cited by 21 publications

(33 citation statements)

References 68 publications

(99 reference statements)

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“…Investigation of the molecular mechanisms underlying the bone destruction in RA has been one of the main thrusts driving the evolution of osteoimmunology. Now, osteoimmunology has become critically important for understanding the pathogenesis of all skeletal diseases associated with abnormal immune responses, including periodontitis and ankylosing spondylitis (Mukai et al 2014). Interestingly, the IL-17 and IL-22 produced by a unique lymphocyte population is critical for ectopic bone formation in the mouse model of ankylosing spondylitis (Sherlock et al 2012).…”

Section: Therapeutic Strategies For Rheumatoid Arthritismentioning

confidence: 99%

Osteoimmunology

Okamoto

Takayanagi

2018

Cold Spring Harb Perspect Med

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Bone is a crucial element of the skeletal-locomotor system, but also functions as an immunological organ that harbors hematopoietic stem cells (HSCs) and immune progenitor cells. Additionally, the skeletal and immune systems share a number of regulatory molecules, including cytokines and signaling molecules. Osteoimmunology was created as an interdisciplinary field to explore the shared molecules and interactions between the skeletal and immune systems. In particular, the importance of an inseparable link between the two systems has been highlighted by studies on the pathogenesis of rheumatoid arthritis (RA), in which pathogenic helper T cells induce the progressive destruction of multiple joints through aberrant expression of receptor activator of nuclear factor (NF)-κB ligand (RANKL). The conceptual bridge of osteoimmunology provides not only a novel framework for understanding these biological systems but also a molecular basis for the development of therapeutic approaches for diseases of bone and/or the immune system.

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Section: Therapeutic Strategies For Rheumatoid Arthritismentioning

confidence: 99%

Osteoimmunology

Okamoto

Takayanagi

2018

Cold Spring Harb Perspect Med

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“…(33)(34)(35) The SH3BP2 gain-of-function mutation also alters the manifestation of autoimmune diseases in mice. (36,37) In contrast, loss-offunction of SH3BP2 suppresses osteoclast function (38,39) and reduces inflammation and joint destruction in mouse models for RA. (39) Thus, investigations from our group have established that SH3BP2 is a regulator of inflammation and osteoclastogenesis and demonstrated that the SH3BP2-SYK axis, as a key signaling pathway in the osteoimmune system, is involved in the pathological mechanisms of common inflammatory arthritis beyond its role in a rare craniofacial disorder.…”

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confidence: 99%

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Kittaka

Yoshimoto

Schlosser

et al. 2019

Journal of Bone and Mineral Research

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Periodontitis is a bacterially induced chronic inflammatory condition of the oral cavity where tooth-supporting tissues including alveolar bone are destructed. Previously, we have shown that the adaptor protein SH3-domain binding protein 2 (SH3BP2) plays a critical role in inflammatory response and osteoclastogenesis of myeloid lineage cells through spleen tyrosine kinase (SYK). In this study, we show that SH3BP2 is a novel regulator for alveolar bone resorption in periodontitis. Micro-CT analysis of SH3BP2-deficient (Sh3bp2 −/− ) mice challenged with ligature-induced periodontitis revealed that Sh3bp2 −/− mice develop decreased alveolar bone loss (male 14.9% AE 10.2%; female 19.0% AE 6.0%) compared with wild-type control mice (male 25.3% AE 5.8%; female 30.8% AE 5.8%). Lack of SH3BP2 did not change the inflammatory cytokine expression and osteoclast induction. Conditional knockout of SH3BP2 and SYK in myeloid lineage cells with LysM-Cre mice recapitulated the reduced bone loss without affecting both inflammatory cytokine expression and osteoclast induction, suggesting that the SH3BP2-SYK axis plays a key role in regulating alveolar bone loss by mechanisms that regulate the bone-resorbing function of osteoclasts rather than differentiation. Administration of a new SYK inhibitor GS-9973 before or after periodontitis induction reduced bone resorption without affecting inflammatory reaction in gingival tissues. In vitro, GS-9973 treatment of bone marrow-derived M-CSF-dependent macrophages suppressed tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation with decreased mineral resorption capacity even when GS-9973 was added after RANKL stimulation. Thus, the data suggest that SH3BP2-SYK is a novel signaling axis for regulating alveolar bone loss in periodontitis and that SYK can be a potential therapeutic target to suppress alveolar bone resorption in periodontal diseases.

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“…Tyrosine phosphorylation of SH3BP2 regulates B cell receptor-mediated activation of nuclear factor of activated T cells [28]. Gain-of-function of SH3BP2 augments inflammation and bone loss by increasing macrophage activation and osteoclast formation [29] while SH3BP2 deficiency inhibits bone loss and the induction of arthritis by disrupting osteoclastogenesis and decreasing autoantibody production [30]. Therefore, modulation of SH3BP2 expression has promising therapeutic potential for the treatment of rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Panax ginseng miRNAs and Their Target Prediction Based on High-Throughput Sequencing

et al. 2019

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Panax ginseng has been widely and effectively used as medicine for thousands of years. However, only limited studies have been conducted to date on ginseng miRNAs. In the present study, we collected 3 ginseng samples from the Changbai Mountain in China. Small RNA libraries were constructed and sequenced on the Illumina HiSeq platform. Sequencing analyses identified 3798 miRNAs, including 298 known miRNAs and 3500 potentially novel miRNAs. The miR166, miR159, and miR396 families were among the most highly expressed miRNAs in all libraries. The results of miRNA expression analyses were validated by qRT-PCR. Target gene prediction through computational and pathway annotation analyses revealed that the primary pathways were related to plant development, including metabolic processes and single-organism processes. It has been reported that plant miRNAs might be one of the hidden bioactive ingredients in medicinal plants. Based on the combined use of RNAhybrid, Miranda, and TargetScan software, a total of 50,992 potential human genes were predicted as the putative targets of 2868 miRNAs. Interestingly, the enriched KEGG pathways were associated with some human diseases, especially cancer, immune system diseases, and neurological disorders, and this could support the clinical use of ginseng. However, the human targets of ginseng miRNAs should be confirmed by further experimental validation. Our results provided valuable insight into ginseng miRNAs and the putative roles of these miRNAs.

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SH3BP2 Gain-Of-Function Mutation Exacerbates Inflammation and Bone Loss in a Murine Collagen-Induced Arthritis Model

Cited by 21 publications

References 68 publications

Osteoimmunology

Osteoimmunology

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Analysis of Panax ginseng miRNAs and Their Target Prediction Based on High-Throughput Sequencing

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