Novel Mutations Causing Isolated Oligodontia.

Hypodontia, i.e., missing one or more teeth, is a relatively common human disease; however, oligodontia, i.

Non-Syndromic Dentinogenesis Imperfecta Caused by Mild Mutations in .

Hereditary dentin defects can be categorized as a syndromic form predominantly related to osteogenesis imperfecta (OI) or isolated forms without other non-oral phenotypes. Mutations in the gene encoding dentin sialophosphoprotein (DSPP) have been identified to cause dentinogenesis imperfecta (DGI) Types II and III and dentin dysplasia (DD) Type II. While DGI Type I is an OI-related syndromic phenotype caused mostly by monoallelic mutations in the genes encoding collagen type I alpha 1 chain () and collagen type I alpha 2 chain ().

The dynactin subunit DCTN1 controls osteoclastogenesis via the Cdc42/PAK2 pathway.

Osteoclasts (OCs), cells specialized for bone resorption, are generated from monocyte/macrophage precursors by a differentiation process governed by RANKL. Here, we show that DCTN1, a key component of the dynactin complex, plays important roles in OC differentiation. The expression of DCTN1 was upregulated by RANKL.

ST5 Positively Regulates Osteoclastogenesis via Src/Syk/calcium Signaling Pathways.

For physiological or pathological understanding of bone disease caused by abnormal behavior of osteoclasts (OCs), functional studies of molecules that regulate the generation and action of OCs are required. In a microarray approach, we found the suppression of tumorigenicity 5 (ST5) gene is upregulated by receptor activator of nuclear factor-κB ligand (RANKL), the OC differentiation factor. Although the roles of ST5 in cancer and β-cells have been reported, the function of ST5 in bone cells has not yet been investigated.

Salt-inducible kinase 1 regulates bone anabolism via the CRTC1-CREB-Id1 axis.

New bone anabolic agents for the effective treatment of bone metabolic diseases like osteoporosis are of high clinical demand. In the present study, we reveal the function of salt-inducible kinase 1 (SIK1) in regulating osteoblast differentiation. Gene knockdown of SIK1 but not of SIK2 or SIK3 expression in primary preosteoblasts increased osteoblast differentiation and bone matrix mineralization.

S100A4 released from highly bone-metastatic breast cancer cells plays a critical role in osteolysis.

Bone destruction induced by breast cancer metastasis causes severe complications, including death, in breast cancer patients. Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis. Tumor-derived factors play fundamental roles in this form of communication.

A CTGF-RUNX2-RANKL Axis in Breast and Prostate Cancer Cells Promotes Tumor Progression in Bone.

Metastasis to bone is a frequent occurrence in patients with breast and prostate cancers and inevitably threatens the patient's quality of life and survival. Identification of cancer-derived mediators of bone metastasis and osteolysis may lead to novel therapeutic strategies. In this study, we established highly bone-metastatic PC3 prostate and MDA-MB-231 (MDA) breast cancer cell sublines by in vivo selection in mice.

Mitofusin 2, a mitochondria-ER tethering protein, facilitates osteoclastogenesis by regulating the calcium-calcineurin-NFATc1 axis.

Mitofusin 2 (Mfn2) is a mitochondrial outer membrane protein that participates in tethering mitochondria to the ER. Mitochondria-ER tethering has been demonstrated to play important roles in many cellular activities by regulating homeostasis of metabolites and calcium. Intracellular calcium signaling is crucial for the differentiation of osteoclasts, the bone-resorbing cells.

Haptoglobin Acts as a TLR4 Ligand to Suppress Osteoclastogenesis via the TLR4-IFN-β Axis.

Haptoglobin (Hp), a type of acute-phase protein, is known to have a systemic anti-inflammatory function and to modulate inflammation by directly affecting immune cells, such as T cells, dendritic cells, and macrophages. However, the effects of Hp on osteoclast differentiation are not well studied, even though osteoclast precursor cells belong to a macrophage-monocyte lineage. In this study, we found that the bone volume was reduced, and the number of osteoclasts was increased in Hp-deficient mice compared with wild-type mice.

Vav1 inhibits RANKL-induced osteoclast differentiation and bone resorption.

Vav1 is a Rho/Rac guanine nucleotide exchange factor primarily expressed in hematopoietic cells. In this study, we investigated the potential role of Vav1 in osteoclast (OC) differentiation by comparing the ability of bone marrow mononuclear cells (BMMCs) obtained from Vav1-deficient (Vav1-/-) and wild-type (WT) mice to differentiate into mature OCs upon stimulation with macrophage colony stimulating factor and receptor activator of nuclear kappa B ligand in vitro. Our results suggested that Vav1 deficiency promoted the differentiation of BMMCs into OCs, as indicated by the increased expression of tartrate-resistant acid phosphatase, cathepsin K, and calcitonin receptor.

Candidate gene sequencing reveals mutations causing hypoplastic amelogenesis imperfecta.

Objective: Amelogenesis imperfecta (AI) is a rare hereditary disorder affecting the quality and quantity of the tooth enamel. The purpose of this study was to identify the genetic etiology of hypoplastic AI families based on the candidate gene approach.

Materials And Methods: We recruited three Turkish families with hypoplastic AI and performed a candidate gene screening based on the characteristic clinical feature to find the pathogenic genetic etiology.

Data on the expression of CXCR3 ligands and pro-inflammatory cytokines in macrophages and CD4 T cells after stimuli of CXCR3 ligands.

C-X-C motif chemokine receptor 3 (CXCR3) is a G protein-coupled receptor for three ligands which are C-X-C motif chemokine 9 (CXCL9), CXCL10, and CXCL11 [1]. Previously we have reported that CXCL10 promotes pro-inflammatory cytokine expression, and forms positive feedback loop [2], [3]. In the present study, we described mRNA expression of CXCL9 and CXCL11 under CXCL10 stimuli in the presence or absence of CXCR3 antagonist, JN-2 in bone marrow-derived macrophages (BMMs) and CD4 T cells.

Trapidil induces osteogenesis by upregulating the signaling of bone morphogenetic proteins.

Platelet-derived growth factor receptor (PDGFR) signaling has been shown to inhibit osteogenesis. However, therapeutic efficacy of inhibiting PDGF signaling to bone regeneration in vivo and the specific mechanisms by which PDGFR signaling inhibits osteogenic differentiation remain unclear. In the present study, we examined the osteogenic effect of inhibiting PDGFR using trapidil, a PDGFR antagonist, in vivo and in vitro, and evaluated its mechanisms.

α-Tocopheryl Succinate Inhibits Osteolytic Bone Metastasis of Breast Cancer by Suppressing Migration of Cancer Cells and Receptor Activator of Nuclear Factor-κB Ligand Expression of Osteoblasts.

Background: Breast cancer is one of the most common cancers affecting women and has a high incidence of bone metastasis, causing osteolytic lesions. The elevated expression of receptor activator of nuclear factor-κB ligand (RANKL) in cancer activates osteoclasts, leading to bone destruction. We previously reported that α-tocopheryl succinate (αTP-suc) inhibited interleukin-1-induced RANKL expression in osteoblasts.

JN-2, a C-X-C motif chemokine receptor 3 antagonist, ameliorates arthritis progression in an animal model.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by uncontrolled joint inflammation and destruction of bone and cartilage. Previous studies have shown that C-X-C motif chemokine 10 (CXCL10) has important roles in RA development and that blocking CXCL10 expression effectively inhibits arthritis progression in animal models. However, clinical study using anti-CXCL10 monoclonal antibody (MDX-1100) to block CXCL10 expression in patients with RA did not show significant effectiveness.

Transglutaminase 2 regulates osteoclast differentiation via a Blimp1-dependent pathway.

Transglutaminase 2 (TG2) performs multiple reactions, including transamidation, and also plays a role in signal transduction as a GTP-binding protein. In this study, we reveal that TG2 controls osteoclast differentiation and bone homeostasis in mice. Osteoclasts specifically expressed the TG2 isoform among eight TG family members.

Stimulation of osteoclast migration and bone resorption by C-C chemokine ligands 19 and 21.

Osteoclasts are responsible for the bone erosion associated with rheumatoid arthritis (RA). The upregulation of the chemokines CCL19 and CCL21 and their receptor CCR7 has been linked to RA pathogenesis. The purpose of this study was to evaluate the effects of CCL19 and CCL21 on osteoclasts and to reveal their underlying mechanisms.

Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by uncontrolled joint inflammation and destruction of bone and cartilage. We previously reported that C-X-C motif chemokine 10 (CXCL10; also called IP-10) has important roles in joint inflammation and bone destruction in arthritis. However, the specific mechanisms by which CXCL10 regulates the recruitment of inflammatory cells and the production of osteoclastogenic cytokines in RA progression are not fully understood.

NF-κB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells.

The chemokine CXCL10 and its receptor CXCR3 play a role in breast cancer metastasis to bone and osteoclast activation. However, the mechanism of CXCL10/CXCR3-induced intracellular signaling has not been fully investigated. To evaluate CXCL10-induced cellular events in the mouse breast cancer cell line 4T1, we developed a new synthetic CXCR3 antagonist JN-2.

A novel AMELX mutation causes hypoplastic amelogenesis imperfecta.

Objectives: Amelogenesis imperfecta (AI) is a hereditary genetic defect affecting tooth enamel. AI is heterogeneous in clinical phenotype as well as in genetic etiology. To date, more than 10 genes have been associated with the etiology of AI.

Extracellular S100A4 negatively regulates osteoblast function by activating the NF-κB pathway.

Patients with inflammatory bone disease or cancer exhibit an increased risk of fractures and delayed bone healing. The S100A4 protein is a member of the calcium-binding S100 protein family, which is abundantly expressed in inflammatory diseases and cancers. We investigated the effects of extracellular S100A4 on osteoblasts, which are cells responsible for bone formation.