Deficiency of Trps1 in Cementoblasts Impairs Cementogenesis and Tooth Root Formation.

Cementum is the least studied of all mineralized tissues and little is known about mechanisms regulating its formation. Therefore, the goal of this study was to provide new insights into the transcriptional regulation of cementum formation by determining the consequences of the deficiency of the Trps1 transcription factor in cementoblasts. We used Trps1 cKO (2.

Antibacterial, biocompatible, and mineralization-inducing properties of calcium silicate-based cements.

Background: Different pulp capping materials have different origins and compositions, require different preparations, and may vary in their bioactive properties.

Aim: The purpose of this study was to evaluate the antibacterial activity, biocompatibility, and mineralization-inducing potential of calcium silicate-based pulp capping materials.

Design: Six contemporary calcium silicate-based cements, ProRoot MTA, MTA Angelus, Biodentine, EndoSequence, NeoMTA 2, and NeoPutty, were evaluated.

Deficiency of Mineralization-Regulating Transcription Factor Trps1 Compromises Quality of Dental Tissues and Increases Susceptibility to Dental Caries.

Dental caries is the most common chronic disease in children and adults worldwide. The complex etiology of dental caries includes environmental factors as well as host genetics, which together contribute to inter-individual variation in susceptibility. The goal of this study was to provide insights into the molecular pathology underlying increased predisposition to dental caries in trichorhinophalangeal syndrome (TRPS).

Trps1 transcription factor represses phosphate-induced expression of SerpinB2 in osteogenic cells.

Serine protease inhibitor SerpinB2 is one of the most upregulated proteins following cellular stress. This multifunctional serpin has been attributed a number of pleiotropic activities, including roles in cell survival, proliferation, differentiation, immunity and extracellular matrix (ECM) remodeling. Studies of cancer cells demonstrated that expression of SerpinB2 is directly repressed by the Trps1 transcription factor, which is a regulator of skeletal and dental tissues mineralization.

Reactive oxygen species (ROS) generation as an underlying mechanism of inorganic phosphate (P)-induced mineralization of osteogenic cells.

Reactive Oxygen Species (ROS) are a natural byproduct of oxygen metabolism. At physiological levels, ROS regulate multiple cellular processes like proliferation, migration, and differentiation. Increased levels of ROS are associated with pathological conditions, such as inflammation and vascular calcification, where they elicit cytotoxic effects.

Trps1 Regulates Development of Craniofacial Skeleton and Is Required for the Initiation of Palatal Shelves Fusion.

Trichorhinophalangeal syndrome (TRPS) is an autosomal dominant disorder resulting from heterozygous mutations of the gene. Common craniofacial abnormalities in TRPS patients include micrognathia, hypoplastic zygomatic arch, high-arched palate, and, occasionally, cleft palate. Studies have demonstrated that mice with a heterozygous mutation ( mice) have similar features to patients with TRPS, including high-arched palates.

Trps1 transcription factor regulates mineralization of dental tissues and proliferation of tooth organ cells.

Mutations of the TRPS1 gene cause trichorhinophalangeal syndrome (TRPS), a skeletal dysplasia with dental abnormalities. TRPS dental phenotypes suggest that TRPS1 regulates multiple aspects of odontogenesis, including the tooth number and size. Previous studies delineating Trps1 expression throughout embryonic tooth development in mice detected strong Trps1 expression in dental mesenchyme, preodontoblasts, and dental follicles, suggesting that TRPS dental phenotypes result from abnormalities in early developmental processes.

Proteomic profiling of extracellular vesicles released from vascular smooth muscle cells during initiation of phosphate-induced mineralization.

Unlabelled: Purpose/Aim: Elevated serum phosphate is one of the major factors contributing to vascular calcification. Studies suggested that extracellular vesicles released from vascular smooth muscle cells significantly contribute to the initiation and progression of this pathology. Recently, we have demonstrated that elevated phosphate stimulates release of extracellular vesicles from osteogenic cells at the initiation of the mineralization process.

Dspp-independent Effects of Transgenic Trps1 Overexpression on Dentin Formation.

The Trps1 transcription factor is highly expressed in dental mesenchyme and preodontoblasts, while in mature, secretory odontoblasts, it is expressed at low levels. Previously, we have shown that high Trps1 levels in mature odontoblasts impair their function in vitro and in vivo. Col1a1-Trps1 transgenic (Trps1-Tg) mice demonstrate defective dentin secretion and mineralization, which are associated with significantly decreased Dspp expression due to direct repression of the Dspp gene by Trps1.

The growth and aggressive behavior of human osteosarcoma is regulated by a CaMKII-controlled autocrine VEGF signaling mechanism.

Osteosarcoma (OS) is a hyperproliferative malignant tumor that requires a high vascular density to maintain its large volume. Vascular Endothelial Growth Factor (VEGF) plays a crucial role in angiogenesis and acts as a paracrine and autocrine agent affecting both endothelial and tumor cells. The alpha-Ca2+/Calmodulin kinase two (α-CaMKII) protein is an important regulator of OS growth.

Specificity protein 7 is not essential for tooth morphogenesis.

Tooth formation is a multifaceted process involving numerous interactions between oral epithelium and neural crest derived ecto-mesenchyme from morphogenesis to cyto-differentiation. The precise molecular regulator that drives the cyto-differentiation and dynamic cross-talk between the two cell types has yet to be fully understood. Runx2 along with its downstream target Sp7 are essential transcription factors for development of the mineralizing cell types.

Dual role of the Trps1 transcription factor in dentin mineralization.

TRPS1 (tricho-rhino-phalangeal syndrome) is a unique GATA-type transcription factor that acts as a transcriptional repressor. TRPS1 deficiency and dysregulated TRPS1 expression result in skeletal and dental abnormalities implicating TRPS1 in endochondral bone formation and tooth development. Moreover, patients with tricho-rhino-phalangeal syndrome frequently present with low bone mass indicating TRPS1 involvement in bone homeostasis.

Differential effects of collagen prolyl 3-hydroxylation on skeletal tissues.

Mutations in the genes encoding cartilage associated protein (CRTAP) and prolyl 3-hydroxylase 1 (P3H1 encoded by LEPRE1) were the first identified causes of recessive Osteogenesis Imperfecta (OI). These proteins, together with cyclophilin B (encoded by PPIB), form a complex that 3-hydroxylates a single proline residue on the α1(I) chain (Pro986) and has cis/trans isomerase (PPIase) activity essential for proper collagen folding. Recent data suggest that prolyl 3-hydroxylation of Pro986 is not required for the structural stability of collagen; however, the absence of this post-translational modification may disrupt protein-protein interactions integral for proper collagen folding and lead to collagen over-modification.

Transcriptional repression of the Dspp gene leads to dentinogenesis imperfecta phenotype in Col1a1-Trps1 transgenic mice.

Dentinogenesis imperfecta (DGI) is a hereditary defect of dentin, a calcified tissue that is the most abundant component of teeth. Most commonly, DGI is manifested as a part of osteogenesis imperfecta (OI) or the phenotype is restricted to dental findings only. In the latter case, DGI is caused by mutations in the DSPP gene, which codes for dentin sialoprotein (DSP) and dentin phosphoprotein (DPP).

Runx2 contributes to murine Col10a1 gene regulation through direct interaction with its cis-enhancer.

We have recently shown that a 150-bp Col10a1 distal promoter (-4296 to -4147 bp) is sufficient to direct hypertrophic chondrocyte-specific reporter (LacZ) expression in vivo. More recently, through detailed sequence analysis we identified two putative tandem-repeat Runx2 binding sites within the 3'-end of this 150-bp region (TGTGGG-TGTGGC, -4187 to -4176 bp). Candidate electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation, and transfection studies demonstrate that these putative Runx2 sites bind Runx2 and mediate upregulated Col10a1/reporter activity in vitro.

Mutations in SERPINF1 cause osteogenesis imperfecta type VI.

Osteogenesis imperfecta (OI) is a spectrum of genetic disorders characterized by bone fragility. It is caused by dominant mutations affecting the synthesis and/or structure of type I procollagen or by recessively inherited mutations in genes responsible for the posttranslational processing/trafficking of type I procollagen. Recessive OI type VI is unique among OI types in that it is characterized by an increased amount of unmineralized osteoid, thereby suggesting a distinct disease mechanism.

Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome.

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and posttranslational modification of type I collagen. Autosomal dominant OI is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Bruck syndrome is a recessive disorder featuring congenital contractures in addition to bone fragility; Bruck syndrome type 2 is caused by mutations in PLOD2 encoding collagen lysyl hydroxylase, whereas Bruck syndrome type 1 has been mapped to chromosome 17, with evidence suggesting region 17p12, but the gene has remained elusive so far.

Localization of the cis-enhancer element for mouse type X collagen expression in hypertrophic chondrocytes in vivo.

The type X collagen gene (Col10a1) is a specific molecular marker of hypertrophic chondrocytes during endochondral bone formation. Mutations in human COL10A1 and altered chondrocyte hypertrophy have been associated with multiple skeletal disorders. However, until recently, the cis-enhancer element that specifies Col10a1 expression in hypertrophic chondrocytes in vivo has remained unidentified.

Tricho-rhino-phalangeal syndrome with supernumerary teeth.

Tricho-rhino-phalangeal syndromes (TRPS) are caused by mutation or deletion of TRPS1, a gene encoding a GATA transcription factor. These disorders are characterized by abnormalities of the hair, face, and selected bones. Rare cases of individuals with TRPS displaying supernumerary teeth have been reported, but none of these has been examined molecularly.

Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome.

Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant craniofacial and skeletal dysplasia that is caused by mutations involving the TRPS1 gene. Patients with TRPS have short stature, hip abnormalities, cone-shaped epiphyses and premature closure of growth plates reflecting defects in endochondral ossification. The TRPS1 gene encodes for the transcription factor TRPS1 that has been demonstrated to repress transcription in vitro.

De novo three-way chromosome translocation 46,XY,t(4;6;21)(p16;p21.1;q21) in a male with cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia associated with cranial, clavicular, and dental anomalies. It is caused by mutations in the RUNX2 gene, which encodes an osteoblast-specific transcription factor and maps to chromosome 6p21. We report clinical and molecular cytogenetic studies in a patient with clinical features of CCD including wormian bones, delayed fontanel closure, hypoplastic clavicles and pubic rami, and supernumerary dentition.

The presence of germ line mosaicism in cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is typically an autosomal dominant condition. The possibility of alternative causes, such as an autosomal recessive form or germ line mosaicism, have been suggested in some families with CCD, but not proven. We present a family consisting of a mother having three sons affected with CCD.

Mutations and promoter SNPs in RUNX2, a transcriptional regulator of bone formation.

Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal malformation syndrome with high penetrance and variable expressivity. It is caused by loss of function mutations in the RUNX2 gene that encodes for a transcription factor essential for osteoblast differentiation and chondrocyte maturation. To identify new pathogenic mutations associated with CCD we screened 38 CCD patients for mutations in the RUNX2 coding sequence.

Characterization of a new syndrome that associates craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, and skin eruption: CDAGS.

We describe the clinical characterization, molecular analyses, and genetic mapping of a distinct genetic condition characterized by craniosynostosis, delayed closure of the fontanel, cranial defects, clavicular hypoplasia, anal and genitourinary malformations, and skin eruption. We have identified seven patients with this phenotype in four families from different geographic regions and ethnic backgrounds. This is an autosomal recessive condition that brings together apparently opposing pathophysiologic and developmental processes, including accelerated suture closure and delayed ossification.