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Ernst J. Reichenberger - One of the best experts on this subject based on the ideXlab platform.
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Microbe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Mice.
JBMR plus, 2020Co-Authors: Mizuho Kittaka, Tetsuya Yoshimoto, Collin Schlosser, Mikihito Kajiya, Hidemi Kurihara, Ernst J. Reichenberger, Yasuyoshi UekiAbstract:Cherubism (OMIM#118400) is a craniofacial disorder characterized by destructive jaw expansion. Gain-of-function mutations in SH3-domain binding protein 2 (SH3BP2) are responsible for this rare disorder. We have previously shown that homozygous knock-in (KI) mice (Sh3bp2 KI/KI ) recapitulate human Cherubism by developing inflammatory lesions in the jaw. However, it remains unknown why heterozygous KI mice (Sh3bp2 KI/+ ) do not recapitulate the excessive jawbone destruction in human Cherubism, even though all mutations are heterozygous in humans. We hypothesized that Sh3bp2 KI/+ mice need to be challenged for developing exacerbated jawbone destruction and that bacterial stimulation in the oral cavity may be involved in the mechanism. In this study, we applied a ligature-induced periodontitis model to Sh3bp2 KI/+ mice to induce inflammatory alveolar bone destruction. Ligature placement induced alveolar bone resorption with gingival inflammation. Quantification of alveolar bone volume revealed that Sh3bp2 KI/+ mice developed more severe bone loss (male: 43.0% ± 10.6%, female: 42.6% ± 10.4%) compared with Sh3bp2 +/+ mice (male: 25.8% ± 4.0%, female: 30.9% ± 6.5%). Measurement of bone loss by the cement-enamel junction-alveolar bone crest distance showed no difference between Sh3bp2 KI/+ and Sh3bp2 +/+ mice. The number of osteoclasts on the alveolar bone surface was higher in male Sh3bp2 KI/+ mice, but not in females, compared with Sh3bp2 +/+ mice. In contrast, inflammatory cytokine levels in gingiva were comparable between Sh3bp2 KI/+ and Sh3bp2 +/+ mice with ligatures. Genetic deletion of the spleen tyrosine kinase in myeloid cells and antibiotic treatment suppressed alveolar bone loss in Sh3bp2 KI/+ mice, suggesting that increased osteoclast differentiation and function mediated by SYK and accumulation of oral bacteria are responsible for the increased alveolar bone loss in Sh3bp2 KI/+ mice with ligature-induced periodontitis. High amounts of oral bacterial load caused by insufficient oral hygiene could be a trigger for the initiation of jawbone destruction in human Cherubism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Investigating global gene expression changes in a murine model of Cherubism
Bone, 2020Co-Authors: Tulika Sharma, Yasuyoshi Ueki, Ernst J. Reichenberger, Justin Cotney, Vijender Singh, Archana Sanjay, Peter MayeAbstract:Cherubism is a rare genetic disorder caused primarily by mutations in SH3BP2 resulting in excessive bone resorption and fibrous tissue overgrowth in the lower portions of the face. Bone marrow derived cell cultures derived from a murine model of Cherubism display poor osteogenesis and spontaneous osteoclast formation. To develop a deeper understanding for the potential underlying mechanisms contributing to these phenotypes in mice, we compared global gene expression changes in hematopoietic and mesenchymal cell populations between Cherubism and wild type mice. In the hematopoietic population, not surprisingly, upregulated genes were significantly enriched for functions related to osteoclastogenesis. However, these upregulated genes were also significantly enriched for functions associated with inflammation including arachidonic acid/prostaglandin signaling, regulators of coagulation and autoinflammation, extracellular matrix remodeling, and chemokine expression. In the mesenchymal population, we observed down regulation of osteoblast and adventitial reticular cell marker genes. Regulators of BMP and Wnt pathway associated genes showed numerous changes in gene expression, likely implicating the down regulation of BMP signaling and possibly the activation of certain Wnt pathways. Analyses of the Cherubism derived mesenchymal population also revealed interesting changes in gene expression related to inflammation including the expression of distinct granzymes, chemokines, and sulfotransferases. These studies reveal complex changes in gene expression elicited from a cherubic mutation in Sh3bp2 that are informative to the mechanisms responding to inflammatory stimuli and repressing osteogenesis. The outcomes of this work are likely to have relevance not only to Cherubism, but other inflammatory conditions impacting the skeleton.
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clinicoradiologic follow up of Cherubism with aggressive characteristics a series of 3 cases
Oral Surgery Oral Medicine Oral Pathology and Oral Radiology, 2019Co-Authors: Sunita Gupta, Ernst J. Reichenberger, Shyam Kishor Sah, Khushboo Singh, Anju Garg, P S Bhandari, Seema Kapoor, Shyama Jain, Nirupama TrehanpatiAbstract:Cherubism is a rare autosomal dominant disorder characterized by replacement of bone with fibrous tissue containing multinucleated giant cells. It manifests as bilateral mandibular and/or maxillary enlargement. The 2017 World Health Organization classification lists Cherubism as a giant cell lesion of the jaws, distinct from fibro-osseous disorders. We discuss 3 cases of familial Cherubism having aggressive characteristics and present clinicoradiologic evaluations of the lesions over 12, 18, and 1.5 years, respectively. Follow-up was observational, without active intervention. Analysis of the lesions for change in size and functional impairments was correlated with periodic imaging. All patients are currently being monitored. The outcome in 2 cases has been excellent without intervention, but 1 case had extensive involvement of the jaws and involvement of the condyle and orbit. A secondary giant cell lesion involved the palate in one patient's mother, who had had cherubic lesions in childhood.
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second generation syk inhibitor entospletinib ameliorates fully established inflammation and bone destruction in the Cherubism mouse model
Journal of Bone and Mineral Research, 2018Co-Authors: Tetsuya Yoshimoto, Mizuho Kittaka, Ernst J. Reichenberger, Tatsuhide Hayashi, Toshio Kondo, Yasuyoshi UekiAbstract:Cherubism is a craniofacial disorder characterized by maxillary and mandibular bone destruction. Gain-of-function mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for the excessive bone resorption caused by fibrous inflammatory lesions. A homozygous knock-in (KI) mouse model for Cherubism (Sh3bp2KI/KI ) develops autoinflammation resulting in systemic bone destruction. Although administration of the TNF-α blocker etanercept to neonatal Sh3bp2KI/KI mice prevented the disease onset, this therapy was not effective for adult Sh3bp2KI/KI mice or human Cherubism patients who already had lesions. Because genetic ablation of spleen tyrosine kinase (SYK) in myeloid cells rescues Sh3bp2KI/KI mice from inflammation, we examined whether SYK inhibitor administration can improve fully developed Cherubism symptoms in adult Sh3bp2KI/KI mice. Entospletinib (GS-9973) was intraperitoneally injected into 10-week-old Sh3bp2KI/KI mice every day for 6 weeks. Treatment with GS-9973 improved facial swelling and histomorphometric analysis of lung and liver tissue showed that GS-9973 administration significantly reduced inflammatory infiltrates associated with decreased levels of serum TNF-α. Micro-computed tomography (μCT) analysis showed that GS-9973 treatment reduced bone erosion in mandibles, calvariae, and ankle and elbow joints of Sh3bp2KI/KI mice compared to Sh3bp2KI/KI mice treated with dimethyl sulfoxide (DMSO). Taken together, the results demonstrate that administration of the SYK inhibitor ameliorates an already established Cherubism phenotype in mice, suggesting that pharmacological inhibition of SYK may be a treatment option for Cherubism patients with active disease progression. © 2018 American Society for Bone and Mineral Research.
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Rescue of a Cherubism bone marrow stromal culture phenotype by reducing TGFβ signaling.
Bone, 2018Co-Authors: Yaling Liu, Yasuyoshi Ueki, Ernst J. Reichenberger, I.-ping Chen, Tulika Sharma, Yumna Arif, Daniel Parisi, Peter MayeAbstract:Abstract We utilized a bone marrow stromal culture system to investigate changes in TGFβ signaling in a mouse model for Cherubism ( Sh3bp2 KI / KI ). Interestingly, bone marrow cultures derived from Cherubism mice not only displayed impaired osteoblast differentiation, but also had spontaneous osteoclast formation. PAI1 , a target gene of TGFβ signaling, was elevated 2-fold in Cherubism CD11b − ,CD45 − cells compared to wild type cells, while the expression of BAMBI, an inhibitor of TGFβ signaling, was down-regulated. We also discovered that treatment of Cherubism cultures with antagonists of the TGFβ signaling pathway could largely rescue osteoblast differentiation and markedly reduce spontaneous osteoclast formation. Treatment with the type I TGFβ receptor small molecule inhibitor SB505124 increased osteoblast reporter gene Col1a1 -2.3 expression 24-fold and increased the expression of osteoblast gene markers Osterix ( Sp7 ) 25-fold, Bone Sialoprotein ( BSP ) 7-fold, Osteocalcin ( Bglap1 ) 100-fold, and Dentin Matrix Protein 1 ( DMP1 ) 35-fold. In contrast, SB505124 treatment resulted in a significant reductions in osteoclast number and size. Gene expression analyses for RANKL, a positive regulator of osteoclast formation was 2.5-fold higher in osteoblast cultures derived from Sh3bp2 KI / KI mice compared to wild type cultures, whereas OPG, an inhibitor of RANKL was 5-fold lower. However, SB505124 treatment reduced RANKL almost back down to wild type levels, while increasing OPG expression. Our studies also implicate a role for TGFβ ligands in the etiology of Cherubism. Blocking of TGFβ ligands with the monoclonal antibody 1D11 increased Col1a1 -2.3 reporter expression 4-fold and 13-fold in cultures derived from Sh3bp2 KI /+ and Sh3bp2 KI / KI mice, respectively. Serum levels of latent TGFβ1 were also 2-fold higher in SH3BP2 KI/KI mice compared to wild type littermates. Taken together, these studies provide evidence that elevated levels of TGFβ signaling may contribute to the disease phenotype of Cherubism and a reduction in pathway activity may be an effective therapeutic approach to treat this rare disease.
Yasuyoshi Ueki - One of the best experts on this subject based on the ideXlab platform.
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Microbe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Mice.
JBMR plus, 2020Co-Authors: Mizuho Kittaka, Tetsuya Yoshimoto, Collin Schlosser, Mikihito Kajiya, Hidemi Kurihara, Ernst J. Reichenberger, Yasuyoshi UekiAbstract:Cherubism (OMIM#118400) is a craniofacial disorder characterized by destructive jaw expansion. Gain-of-function mutations in SH3-domain binding protein 2 (SH3BP2) are responsible for this rare disorder. We have previously shown that homozygous knock-in (KI) mice (Sh3bp2 KI/KI ) recapitulate human Cherubism by developing inflammatory lesions in the jaw. However, it remains unknown why heterozygous KI mice (Sh3bp2 KI/+ ) do not recapitulate the excessive jawbone destruction in human Cherubism, even though all mutations are heterozygous in humans. We hypothesized that Sh3bp2 KI/+ mice need to be challenged for developing exacerbated jawbone destruction and that bacterial stimulation in the oral cavity may be involved in the mechanism. In this study, we applied a ligature-induced periodontitis model to Sh3bp2 KI/+ mice to induce inflammatory alveolar bone destruction. Ligature placement induced alveolar bone resorption with gingival inflammation. Quantification of alveolar bone volume revealed that Sh3bp2 KI/+ mice developed more severe bone loss (male: 43.0% ± 10.6%, female: 42.6% ± 10.4%) compared with Sh3bp2 +/+ mice (male: 25.8% ± 4.0%, female: 30.9% ± 6.5%). Measurement of bone loss by the cement-enamel junction-alveolar bone crest distance showed no difference between Sh3bp2 KI/+ and Sh3bp2 +/+ mice. The number of osteoclasts on the alveolar bone surface was higher in male Sh3bp2 KI/+ mice, but not in females, compared with Sh3bp2 +/+ mice. In contrast, inflammatory cytokine levels in gingiva were comparable between Sh3bp2 KI/+ and Sh3bp2 +/+ mice with ligatures. Genetic deletion of the spleen tyrosine kinase in myeloid cells and antibiotic treatment suppressed alveolar bone loss in Sh3bp2 KI/+ mice, suggesting that increased osteoclast differentiation and function mediated by SYK and accumulation of oral bacteria are responsible for the increased alveolar bone loss in Sh3bp2 KI/+ mice with ligature-induced periodontitis. High amounts of oral bacterial load caused by insufficient oral hygiene could be a trigger for the initiation of jawbone destruction in human Cherubism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Investigating global gene expression changes in a murine model of Cherubism
Bone, 2020Co-Authors: Tulika Sharma, Yasuyoshi Ueki, Ernst J. Reichenberger, Justin Cotney, Vijender Singh, Archana Sanjay, Peter MayeAbstract:Cherubism is a rare genetic disorder caused primarily by mutations in SH3BP2 resulting in excessive bone resorption and fibrous tissue overgrowth in the lower portions of the face. Bone marrow derived cell cultures derived from a murine model of Cherubism display poor osteogenesis and spontaneous osteoclast formation. To develop a deeper understanding for the potential underlying mechanisms contributing to these phenotypes in mice, we compared global gene expression changes in hematopoietic and mesenchymal cell populations between Cherubism and wild type mice. In the hematopoietic population, not surprisingly, upregulated genes were significantly enriched for functions related to osteoclastogenesis. However, these upregulated genes were also significantly enriched for functions associated with inflammation including arachidonic acid/prostaglandin signaling, regulators of coagulation and autoinflammation, extracellular matrix remodeling, and chemokine expression. In the mesenchymal population, we observed down regulation of osteoblast and adventitial reticular cell marker genes. Regulators of BMP and Wnt pathway associated genes showed numerous changes in gene expression, likely implicating the down regulation of BMP signaling and possibly the activation of certain Wnt pathways. Analyses of the Cherubism derived mesenchymal population also revealed interesting changes in gene expression related to inflammation including the expression of distinct granzymes, chemokines, and sulfotransferases. These studies reveal complex changes in gene expression elicited from a cherubic mutation in Sh3bp2 that are informative to the mechanisms responding to inflammatory stimuli and repressing osteogenesis. The outcomes of this work are likely to have relevance not only to Cherubism, but other inflammatory conditions impacting the skeleton.
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second generation syk inhibitor entospletinib ameliorates fully established inflammation and bone destruction in the Cherubism mouse model
Journal of Bone and Mineral Research, 2018Co-Authors: Tetsuya Yoshimoto, Mizuho Kittaka, Ernst J. Reichenberger, Tatsuhide Hayashi, Toshio Kondo, Yasuyoshi UekiAbstract:Cherubism is a craniofacial disorder characterized by maxillary and mandibular bone destruction. Gain-of-function mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for the excessive bone resorption caused by fibrous inflammatory lesions. A homozygous knock-in (KI) mouse model for Cherubism (Sh3bp2KI/KI ) develops autoinflammation resulting in systemic bone destruction. Although administration of the TNF-α blocker etanercept to neonatal Sh3bp2KI/KI mice prevented the disease onset, this therapy was not effective for adult Sh3bp2KI/KI mice or human Cherubism patients who already had lesions. Because genetic ablation of spleen tyrosine kinase (SYK) in myeloid cells rescues Sh3bp2KI/KI mice from inflammation, we examined whether SYK inhibitor administration can improve fully developed Cherubism symptoms in adult Sh3bp2KI/KI mice. Entospletinib (GS-9973) was intraperitoneally injected into 10-week-old Sh3bp2KI/KI mice every day for 6 weeks. Treatment with GS-9973 improved facial swelling and histomorphometric analysis of lung and liver tissue showed that GS-9973 administration significantly reduced inflammatory infiltrates associated with decreased levels of serum TNF-α. Micro-computed tomography (μCT) analysis showed that GS-9973 treatment reduced bone erosion in mandibles, calvariae, and ankle and elbow joints of Sh3bp2KI/KI mice compared to Sh3bp2KI/KI mice treated with dimethyl sulfoxide (DMSO). Taken together, the results demonstrate that administration of the SYK inhibitor ameliorates an already established Cherubism phenotype in mice, suggesting that pharmacological inhibition of SYK may be a treatment option for Cherubism patients with active disease progression. © 2018 American Society for Bone and Mineral Research.
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Rescue of a Cherubism bone marrow stromal culture phenotype by reducing TGFβ signaling.
Bone, 2018Co-Authors: Yaling Liu, Yasuyoshi Ueki, Ernst J. Reichenberger, I.-ping Chen, Tulika Sharma, Yumna Arif, Daniel Parisi, Peter MayeAbstract:Abstract We utilized a bone marrow stromal culture system to investigate changes in TGFβ signaling in a mouse model for Cherubism ( Sh3bp2 KI / KI ). Interestingly, bone marrow cultures derived from Cherubism mice not only displayed impaired osteoblast differentiation, but also had spontaneous osteoclast formation. PAI1 , a target gene of TGFβ signaling, was elevated 2-fold in Cherubism CD11b − ,CD45 − cells compared to wild type cells, while the expression of BAMBI, an inhibitor of TGFβ signaling, was down-regulated. We also discovered that treatment of Cherubism cultures with antagonists of the TGFβ signaling pathway could largely rescue osteoblast differentiation and markedly reduce spontaneous osteoclast formation. Treatment with the type I TGFβ receptor small molecule inhibitor SB505124 increased osteoblast reporter gene Col1a1 -2.3 expression 24-fold and increased the expression of osteoblast gene markers Osterix ( Sp7 ) 25-fold, Bone Sialoprotein ( BSP ) 7-fold, Osteocalcin ( Bglap1 ) 100-fold, and Dentin Matrix Protein 1 ( DMP1 ) 35-fold. In contrast, SB505124 treatment resulted in a significant reductions in osteoclast number and size. Gene expression analyses for RANKL, a positive regulator of osteoclast formation was 2.5-fold higher in osteoblast cultures derived from Sh3bp2 KI / KI mice compared to wild type cultures, whereas OPG, an inhibitor of RANKL was 5-fold lower. However, SB505124 treatment reduced RANKL almost back down to wild type levels, while increasing OPG expression. Our studies also implicate a role for TGFβ ligands in the etiology of Cherubism. Blocking of TGFβ ligands with the monoclonal antibody 1D11 increased Col1a1 -2.3 reporter expression 4-fold and 13-fold in cultures derived from Sh3bp2 KI /+ and Sh3bp2 KI / KI mice, respectively. Serum levels of latent TGFβ1 were also 2-fold higher in SH3BP2 KI/KI mice compared to wild type littermates. Taken together, these studies provide evidence that elevated levels of TGFβ signaling may contribute to the disease phenotype of Cherubism and a reduction in pathway activity may be an effective therapeutic approach to treat this rare disease.
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Molecular and Cellular Pathogenesis of Cherubism
Clinical calcium, 2016Co-Authors: Yasuyoshi UekiAbstract:Study of rare genetic disorder often provides fundamental insights into the pathology of common diseases. Cherubism is a rare craniofacial disorder in children characterized by the destruction of maxillary and mandibular bones due to expansile fibrous inflammatory lesions. Genetic study of Cherubism families discovered that gain-of-function mutations in the signaling adaptor protein SH3BP2 are responsible for Cherubism. Analysis of the mouse model revealed that Cherubism is an autoinflammatory disorder that is caused by dysregulated signaling pathway mediated by toll-like receptors and spleen tyrosine kinase. Recent study of the SH3BP2-deficient mice showed that SH3BP2 plays important roles in bone resorption in mouse models of inflammatory arthritis. These results establish SH3BP2 as a key player in the osteoimmune system beyond its role in a rare inherited disorder and suggest that the signaling pathway mediated by SH3BP2 is involved in the pathogenesis of common inflammatory bone diseases such as rheumatoid arthritis.
Mizuho Kittaka - One of the best experts on this subject based on the ideXlab platform.
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Microbe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Mice.
JBMR plus, 2020Co-Authors: Mizuho Kittaka, Tetsuya Yoshimoto, Collin Schlosser, Mikihito Kajiya, Hidemi Kurihara, Ernst J. Reichenberger, Yasuyoshi UekiAbstract:Cherubism (OMIM#118400) is a craniofacial disorder characterized by destructive jaw expansion. Gain-of-function mutations in SH3-domain binding protein 2 (SH3BP2) are responsible for this rare disorder. We have previously shown that homozygous knock-in (KI) mice (Sh3bp2 KI/KI ) recapitulate human Cherubism by developing inflammatory lesions in the jaw. However, it remains unknown why heterozygous KI mice (Sh3bp2 KI/+ ) do not recapitulate the excessive jawbone destruction in human Cherubism, even though all mutations are heterozygous in humans. We hypothesized that Sh3bp2 KI/+ mice need to be challenged for developing exacerbated jawbone destruction and that bacterial stimulation in the oral cavity may be involved in the mechanism. In this study, we applied a ligature-induced periodontitis model to Sh3bp2 KI/+ mice to induce inflammatory alveolar bone destruction. Ligature placement induced alveolar bone resorption with gingival inflammation. Quantification of alveolar bone volume revealed that Sh3bp2 KI/+ mice developed more severe bone loss (male: 43.0% ± 10.6%, female: 42.6% ± 10.4%) compared with Sh3bp2 +/+ mice (male: 25.8% ± 4.0%, female: 30.9% ± 6.5%). Measurement of bone loss by the cement-enamel junction-alveolar bone crest distance showed no difference between Sh3bp2 KI/+ and Sh3bp2 +/+ mice. The number of osteoclasts on the alveolar bone surface was higher in male Sh3bp2 KI/+ mice, but not in females, compared with Sh3bp2 +/+ mice. In contrast, inflammatory cytokine levels in gingiva were comparable between Sh3bp2 KI/+ and Sh3bp2 +/+ mice with ligatures. Genetic deletion of the spleen tyrosine kinase in myeloid cells and antibiotic treatment suppressed alveolar bone loss in Sh3bp2 KI/+ mice, suggesting that increased osteoclast differentiation and function mediated by SYK and accumulation of oral bacteria are responsible for the increased alveolar bone loss in Sh3bp2 KI/+ mice with ligature-induced periodontitis. High amounts of oral bacterial load caused by insufficient oral hygiene could be a trigger for the initiation of jawbone destruction in human Cherubism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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second generation syk inhibitor entospletinib ameliorates fully established inflammation and bone destruction in the Cherubism mouse model
Journal of Bone and Mineral Research, 2018Co-Authors: Tetsuya Yoshimoto, Mizuho Kittaka, Ernst J. Reichenberger, Tatsuhide Hayashi, Toshio Kondo, Yasuyoshi UekiAbstract:Cherubism is a craniofacial disorder characterized by maxillary and mandibular bone destruction. Gain-of-function mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for the excessive bone resorption caused by fibrous inflammatory lesions. A homozygous knock-in (KI) mouse model for Cherubism (Sh3bp2KI/KI ) develops autoinflammation resulting in systemic bone destruction. Although administration of the TNF-α blocker etanercept to neonatal Sh3bp2KI/KI mice prevented the disease onset, this therapy was not effective for adult Sh3bp2KI/KI mice or human Cherubism patients who already had lesions. Because genetic ablation of spleen tyrosine kinase (SYK) in myeloid cells rescues Sh3bp2KI/KI mice from inflammation, we examined whether SYK inhibitor administration can improve fully developed Cherubism symptoms in adult Sh3bp2KI/KI mice. Entospletinib (GS-9973) was intraperitoneally injected into 10-week-old Sh3bp2KI/KI mice every day for 6 weeks. Treatment with GS-9973 improved facial swelling and histomorphometric analysis of lung and liver tissue showed that GS-9973 administration significantly reduced inflammatory infiltrates associated with decreased levels of serum TNF-α. Micro-computed tomography (μCT) analysis showed that GS-9973 treatment reduced bone erosion in mandibles, calvariae, and ankle and elbow joints of Sh3bp2KI/KI mice compared to Sh3bp2KI/KI mice treated with dimethyl sulfoxide (DMSO). Taken together, the results demonstrate that administration of the SYK inhibitor ameliorates an already established Cherubism phenotype in mice, suggesting that pharmacological inhibition of SYK may be a treatment option for Cherubism patients with active disease progression. © 2018 American Society for Bone and Mineral Research.
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sh3bp2 Cherubism mutation potentiates tnf α induced osteoclastogenesis via nfatc1 and tnf α mediated inflammatory bone loss
Journal of Bone and Mineral Research, 2014Co-Authors: Tomoyuki Mukai, Shu Ishida, Mizuho Kittaka, Teruhito Yoshitaka, Robert Rottapel, Remi Ishikawa, Richard Gallant, Yi Ling Lin, Marco Brotto, Ernst J. ReichenbergerAbstract:Cherubism (OMIM# 118400) is a genetic disorder with excessive jawbone resorption caused by mutations in SH3 domain binding protein 2 (SH3BP2), a signaling adaptor protein. Studies on the mouse model for Cherubism carrying a P416R knock-in (KI) mutation have revealed that mutant SH3BP2 enhances tumor necrosis factor (TNF)-α production and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation in myeloid cells. TNF-α is expressed in human Cherubism lesions, which contain a large number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, and TNF-α plays a critical role in inflammatory bone destruction in homozygous Cherubism mice (Sh3bp2(KI/KI) ). The data suggest a pathophysiological relationship between mutant SH3BP2 and TNF-α-mediated bone loss by osteoclasts. Therefore, we investigated whether P416R mutant SH3BP2 is involved in TNF-α-mediated osteoclast formation and bone loss. Here, we show that bone marrow-derived M-CSF-dependent macrophages (BMMs) from the heterozygous Cherubism mutant (Sh3bp2(KI/+) ) mice are highly responsive to TNF-α and can differentiate into osteoclasts independently of RANKL in vitro by a mechanism that involves spleen tyrosine kinase (SYK) and phospholipase Cγ2 (PLCγ2) phosphorylation, leading to increased nuclear translocation of NFATc1. The heterozygous Cherubism mutation exacerbates bone loss with increased osteoclast formation in a mouse calvarial TNF-α injection model as well as in a human TNF-α transgenic mouse model (hTNFtg). SH3BP2 knockdown in RAW264.7 cells results in decreased TRAP-positive multinucleated cell formation. These findings suggest that the SH3BP2 Cherubism mutation can cause jawbone destruction by promoting osteoclast formation in response to TNF-α expressed in Cherubism lesions and that SH3BP2 is a key regulator for TNF-α-induced osteoclastogenesis. Inhibition of SH3BP2 expression in osteoclast progenitors could be a potential strategy for the treatment of bone loss in Cherubism as well as in other inflammatory bone disorders.
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Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock-in Cherubism mice.
Bone, 2014Co-Authors: Teruhito Yoshitaka, Tomoyuki Mukai, Shu Ishida, Mizuho Kittaka, Noriyoshi Mizuno, Yasuyoshi UekiAbstract:Cherubism (OMIM#118400) is a genetic disorder in children characterized by excessive jawbone destruction with proliferation of fibro-osseous lesions containing a large number of osteoclasts. Mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for Cherubism. Analysis of the knock-in (KI) mouse model of Cherubism showed that homozygous Cherubism mice (Sh3bp2(KI/KI)) spontaneously develop systemic autoinflammation and inflammatory bone loss and that Cherubism is a TNF-α-dependent hematopoietic disorder. In this study, we investigated whether bone marrow transplantation (BMT) is effective for the treatment of inflammation and bone loss in Sh3bp2(KI/KI) mice. Bone marrow (BM) cells from wild-type (Sh3bp2(+/+)) mice were transplanted to 6-week-old Sh3bp2(KI/KI) mice with developing inflammation and to 10-week-old Sh3bp2(KI/KI) mice with established inflammation. Six-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells exhibited improved body weight loss, facial swelling, and survival rate. Inflammatory lesions in the liver and lung as well as bone loss in calvaria and mandibula were ameliorated at 10weeks after BMT compared to Sh3bp2(KI/KI) mice transplanted with Sh3bp2(KI/KI) BM cells. Elevation of serum TNF-α levels was not detected after BMT. BMT was effective for up to 20weeks in 6-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells. BMT also ameliorated the inflammation and bone loss in 10-week-old Sh3bp2(KI/KI) mice. Thus our study demonstrates that BMT improves the inflammation and bone loss in Cherubism mice. BMT may be effective for the treatment of Cherubism patients.
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Enhanced TLR-MYD88 Signaling Stimulates Autoinflammation in SH3BP2 Cherubism Mice and Defines the Etiology of Cherubism
Cell reports, 2014Co-Authors: Teruhito Yoshitaka, Tomoyuki Mukai, Shu Ishida, Mizuho Kittaka, Noriyoshi Mizuno, Lisa M. Alford, Salome Masrani, Ken Yamaguchi, Motohiko Yamada, Björn OlsenAbstract:Cherubism is caused by mutations in SH3BP2. Studies of Cherubism mice showed that tumor necrosis factor α (TNF-α)-dependent autoinflammation is a major cause of the disorder but failed to explain why human Cherubism lesions are restricted to jaws and regress after puberty. We demonstrate that the inflammation in Cherubism mice is MYD88 dependent and is rescued in the absence of TLR2 and TLR4. However, germ-free Cherubism mice also develop inflammation. Mutant macrophages are hyperresponsive to PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) that activate Toll-like receptors (TLRs), resulting in TNF-α overproduction. Phosphorylation of SH3BP2 at Y183 is critical for the TNF-α production. Finally, SYK depletion in macrophages prevents the inflammation. These data suggest that the presence of a large amount of TLR ligands, presumably oral bacteria and DAMPs during jawbone remodeling, may cause the jaw-specific development of human Cherubism lesions. Reduced levels of DAMPs after stabilization of jaw remodeling may contribute to the age-dependent regression.
Michael A. Levine - One of the best experts on this subject based on the ideXlab platform.
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The role of SH3BP2 in the pathophysiology of Cherubism
Orphanet Journal of Rare Diseases, 2012Co-Authors: Ernst J. Reichenberger, Michael A. Levine, Bjorn R Olsen, Maria E Papadaki, Steven A. LietmanAbstract:Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with Cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of Cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for Cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.
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Cherubism: best clinical practice
Orphanet Journal of Rare Diseases, 2012Co-Authors: Maria E Papadaki, Michael A. Levine, Steven A. Lietman, Bjorn R Olsen, Leonard B Kaban, Ernst J. ReichenbergerAbstract:Cherubism is a skeletal dysplasia characterized by bilateral and symmetric fibro-osseous lesions limited to the mandible and maxilla. In most patients, Cherubism is due to dominant mutations in the SH3BP2 gene on chromosome 4p16.3. Affected children appear normal at birth. Swelling of the jaws usually appears between 2 and 7 years of age, after which, lesions proliferate and increase in size until puberty. The lesions subsequently begin to regress, fill with bone and remodel until age 30, when they are frequently not detectable. Fibro-osseous lesions, including those in Cherubism have been classified as quiescent, non-aggressive and aggressive on the basis of clinical behavior and radiographic findings. Quiescent cherubic lesions are usually seen in older patients and do not demonstrate progressive growth. Non-aggressive lesions are most frequently present in teenagers. Lesions in the aggressive form of Cherubism occur in young children and are large, rapidly growing and may cause tooth displacement, root resorption, thinning and perforation of cortical bone. Because Cherubism is usually self-limiting, operative treatment may not be necessary. Longitudinal observation and follow-up is the initial management in most cases. Surgical intervention with curettage, contouring or resection may be indicated for functional or aesthetic reasons. Surgical procedures are usually performed when the disease becomes quiescent. Aggressive lesions that cause severe functional problems such as airway obstruction justify early surgical intervention.
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SH3BP2 is rarely mutated in exon 9 in giant cell lesions outside Cherubism
Clinical orthopaedics and related research, 2007Co-Authors: Steven A. Lietman, Nichole Prescott, David G. Hicks, William H. Westra, Michael A. LevineAbstract:Giant cell tumor of bone and giant cell reparative granuloma are benign lesions with prominent giant (multinucleated) cells, and an understanding of the molecular biology and genetics of these lesions will likely aid in more effective treatment. Cherubism is a benign lesion of the maxilla and mandible histologically similar to giant cell tumor of bone and giant cell reparative granuloma. Germline mutations in exon 9 of the gene encoding Src homology 3 binding protein 2 (SH3BP2) occur in most patients with Cherubism. We therefore hypothesized SH3BP2 and its putative downstream effector nuclear factor of activated T cells c1 isoform (NFATc1) are highly expressed in sporadic nonsyndromic giant cell lesions and associated with somatic SH3BP2 mutations. We analyzed giant cell lesions for SH3BP2 and NFATc1 expression by RNA blot and/or immunohistochemistry and for exon 9 SH3BP2 mutations. We found the SH3BP2 transcripts and protein were abundantly expressed in giant cell tumors of bone, as well as NFATc1 protein. Sequencing of exon 9 of SH3BP2 was normal in all sporadic nonsyndromic giant cell lesions. Although many multinucleated giant cell lesions of bone share histologic features, the primary genetic defect in Cherubism and these other giant cell lesions appears different.
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identification of a novel mutation of sh3bp2 in Cherubism and demonstration that sh3bp2 mutations lead to increased nfat activation
Human Mutation, 2006Co-Authors: Steven A. Lietman, Michael A. Levine, Natasha Kalinchinko, Xichao Deng, Ronald A KohanskiAbstract:We describe a novel missense mutation (Aspartic acid to Asparagine, p.D419N (g.1371G>A, c.1255G>A) within exon 9 of SH3BP2 in a patient with Cherubism, an autosomal dominant syndrome characterized by excessive osteoclastic bone resorption of the jaw. Two siblings and the father were carriers but lacked phenotypic features. Transient expression of p.D419N (c.1255G>A), as well as three previously described exon 9 mutations from Cherubism patients (p.R415Q (c.1244G>A), p.D420E (c.1259G>A), and p.P418R (c.1253C>G)) increased activity of NFAT (nuclear factor of activated T-cells), an osteoclastogenic mediator, indicating that Cherubism results from gain of function mutations in SH3BP2.
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sh3bp2 Cherubism mutation potentiates tnf α induced osteoclastogenesis via nfatc1 and tnf α mediated inflammatory bone loss
Journal of Bone and Mineral Research, 2014Co-Authors: Tomoyuki Mukai, Shu Ishida, Mizuho Kittaka, Teruhito Yoshitaka, Robert Rottapel, Remi Ishikawa, Richard Gallant, Yi Ling Lin, Marco Brotto, Ernst J. ReichenbergerAbstract:Cherubism (OMIM# 118400) is a genetic disorder with excessive jawbone resorption caused by mutations in SH3 domain binding protein 2 (SH3BP2), a signaling adaptor protein. Studies on the mouse model for Cherubism carrying a P416R knock-in (KI) mutation have revealed that mutant SH3BP2 enhances tumor necrosis factor (TNF)-α production and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation in myeloid cells. TNF-α is expressed in human Cherubism lesions, which contain a large number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, and TNF-α plays a critical role in inflammatory bone destruction in homozygous Cherubism mice (Sh3bp2(KI/KI) ). The data suggest a pathophysiological relationship between mutant SH3BP2 and TNF-α-mediated bone loss by osteoclasts. Therefore, we investigated whether P416R mutant SH3BP2 is involved in TNF-α-mediated osteoclast formation and bone loss. Here, we show that bone marrow-derived M-CSF-dependent macrophages (BMMs) from the heterozygous Cherubism mutant (Sh3bp2(KI/+) ) mice are highly responsive to TNF-α and can differentiate into osteoclasts independently of RANKL in vitro by a mechanism that involves spleen tyrosine kinase (SYK) and phospholipase Cγ2 (PLCγ2) phosphorylation, leading to increased nuclear translocation of NFATc1. The heterozygous Cherubism mutation exacerbates bone loss with increased osteoclast formation in a mouse calvarial TNF-α injection model as well as in a human TNF-α transgenic mouse model (hTNFtg). SH3BP2 knockdown in RAW264.7 cells results in decreased TRAP-positive multinucleated cell formation. These findings suggest that the SH3BP2 Cherubism mutation can cause jawbone destruction by promoting osteoclast formation in response to TNF-α expressed in Cherubism lesions and that SH3BP2 is a key regulator for TNF-α-induced osteoclastogenesis. Inhibition of SH3BP2 expression in osteoclast progenitors could be a potential strategy for the treatment of bone loss in Cherubism as well as in other inflammatory bone disorders.
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Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock-in Cherubism mice.
Bone, 2014Co-Authors: Teruhito Yoshitaka, Tomoyuki Mukai, Shu Ishida, Mizuho Kittaka, Noriyoshi Mizuno, Yasuyoshi UekiAbstract:Cherubism (OMIM#118400) is a genetic disorder in children characterized by excessive jawbone destruction with proliferation of fibro-osseous lesions containing a large number of osteoclasts. Mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for Cherubism. Analysis of the knock-in (KI) mouse model of Cherubism showed that homozygous Cherubism mice (Sh3bp2(KI/KI)) spontaneously develop systemic autoinflammation and inflammatory bone loss and that Cherubism is a TNF-α-dependent hematopoietic disorder. In this study, we investigated whether bone marrow transplantation (BMT) is effective for the treatment of inflammation and bone loss in Sh3bp2(KI/KI) mice. Bone marrow (BM) cells from wild-type (Sh3bp2(+/+)) mice were transplanted to 6-week-old Sh3bp2(KI/KI) mice with developing inflammation and to 10-week-old Sh3bp2(KI/KI) mice with established inflammation. Six-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells exhibited improved body weight loss, facial swelling, and survival rate. Inflammatory lesions in the liver and lung as well as bone loss in calvaria and mandibula were ameliorated at 10weeks after BMT compared to Sh3bp2(KI/KI) mice transplanted with Sh3bp2(KI/KI) BM cells. Elevation of serum TNF-α levels was not detected after BMT. BMT was effective for up to 20weeks in 6-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells. BMT also ameliorated the inflammation and bone loss in 10-week-old Sh3bp2(KI/KI) mice. Thus our study demonstrates that BMT improves the inflammation and bone loss in Cherubism mice. BMT may be effective for the treatment of Cherubism patients.
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Enhanced TLR-MYD88 Signaling Stimulates Autoinflammation in SH3BP2 Cherubism Mice and Defines the Etiology of Cherubism
Cell reports, 2014Co-Authors: Teruhito Yoshitaka, Tomoyuki Mukai, Shu Ishida, Mizuho Kittaka, Noriyoshi Mizuno, Lisa M. Alford, Salome Masrani, Ken Yamaguchi, Motohiko Yamada, Björn OlsenAbstract:Cherubism is caused by mutations in SH3BP2. Studies of Cherubism mice showed that tumor necrosis factor α (TNF-α)-dependent autoinflammation is a major cause of the disorder but failed to explain why human Cherubism lesions are restricted to jaws and regress after puberty. We demonstrate that the inflammation in Cherubism mice is MYD88 dependent and is rescued in the absence of TLR2 and TLR4. However, germ-free Cherubism mice also develop inflammation. Mutant macrophages are hyperresponsive to PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) that activate Toll-like receptors (TLRs), resulting in TNF-α overproduction. Phosphorylation of SH3BP2 at Y183 is critical for the TNF-α production. Finally, SYK depletion in macrophages prevents the inflammation. These data suggest that the presence of a large amount of TLR ligands, presumably oral bacteria and DAMPs during jawbone remodeling, may cause the jaw-specific development of human Cherubism lesions. Reduced levels of DAMPs after stabilization of jaw remodeling may contribute to the age-dependent regression.
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Etanercept administration to neonatal SH3BP2 knock-in Cherubism mice prevents TNF-α-induced inflammation and bone loss.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2014Co-Authors: Teruhito Yoshitaka, Tomoyuki Mukai, Shu Ishida, Mizuho Kittaka, Ernst J. Reichenberger, Yasuyoshi UekiAbstract:Cherubism is a genetic disorder of the craniofacial skeleton caused by gain-of-function mutations in the signaling adaptor protein, SH3-domain binding protein 2 (SH3BP2). In a knock-in mouse model for Cherubism, we previously demonstrated that homozygous mutant mice develop T/B cell–independent systemic macrophage inflammation leading to bone erosion and joint destruction. Homozygous mice develop multiostotic bone lesions whereas Cherubism lesions in humans are limited to jawbones. We identified a critical role of tumor necrosis factor α (TNF-α) in the development of autoinflammation by creating homozygous TNF-α-deficient Cherubism mutants, in which systemic inflammation and bone destruction were rescued. In this study, we examined whether postnatal administration of an anti-TNF-α antagonist can prevent or ameliorate the disease progression in Cherubism mice. Neonatal homozygous mutants, in which active inflammation has not yet developed, were treated with a high dose of etanercept (25 mg/kg, twice/week) for 7 weeks. Etanercept-treated neonatal mice showed strong rescue of facial swelling and bone loss in jaws and calvariae. Destruction of joints was fully rescued in the high-dose group. Moreover, the high-dose treatment group showed a significant decrease in lung and liver inflammatory lesions. However, inflammation and bone loss, which were successfully treated by etanercept administration, recurred after etanercept discontinuation. No significant effect was observed in low-dose–treated (0.5 mg/kg, twice/week) and vehicle-treated groups. In contrast, when 10-week-old Cherubism mice with fully active inflammation were treated with etanercept for 7 weeks, even the high-dose administration did not decrease bone loss or lung or liver inflammation. Taken together, the results suggest that anti-TNF-α therapy may be effective in young Cherubism patients, if treated before the inflammatory phase or bone resorption occurs. Therefore, early genetic diagnosis and early treatment with anti-TNF-α antagonists may be able to prevent or ameliorate Cherubism, especially in patients with a mutation in SH3BP2. © 2014 American Society for Bone and Mineral Research.