Hector F. Rios

Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism

The osteocyte, a terminally differentiated cell comprising 90%–95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (Pi) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.

periostin null mice exhibit dwarfism, incisor enamel defects, and an early-onset periodontal disease-like phenotype

ABSTRACT Periostin was originally identified as an osteoblast-specific factor and is highly expressed in the embryonic periosteum, cardiac valves, placenta, and periodontal ligament as well as in many adult cancerous tissues. To investigate its role during development, we generated mice that lack the periostin gene and replaced the translation start site and first exon with a lacZ reporter gene. Surprisingly, although periostin is widely expressed in many developing organs, periostin-deficient (peri lacZ ) embryos are grossly normal. Postnatally, however, ∼14% of the nulls die before weaning and all of the remaining peri lacZ nulls are severely growth retarded. Skeletal analysis revealed that trabecular bone in adult homozygous skeletons was sparse, but overall bone growth was unaffected. Furthermore, by 3 months, the nulls develop an early-onset periodontal disease-like phenotype. Unexpectedly, these mice also show a severe incisor enamel defect, although there is no apparent change in ameloblast differentiation. Significantly, placing the peri lacZ nulls on a soft diet that alleviated mechanical strain on the periodontal ligament resulted in a partial rescue of both the enamel and periodontal disease-like phenotypes. Combined, these data suggest that a healthy periodontal ligament is required for normal amelogenesis and that periostin is critically required for maintenance of the integrity of the periodontal ligament in response to mechanical stresses.

DMP1 Depletion Decreases Bone Mineralization In Vivo: An FTIR Imaging Analysis†

The role of DMP1 in mineralization was analyzed by comparing bone mineral and matrix properties in dmp1‐null female mice to heterozygous and wildtype controls by FTIR imaging spectroscopy. The observed decreased mineral content in dmp1 null mice indicates a key role for dmp1 in bone mineralization. Indirect effects of DMP1 on other systems also determine the KO phenotype.

Use of cone beam computed tomography in implant dentistry: the International Congress of Oral Implantologists consensus report.

Purpose: The International Congress of Oral Implantologists has supported the development of this consensus report involving the use of Cone Beam Computed Tomography (CBCT) in implant dentistry with the intent of providing scientifically based guidance to clinicians regarding its use as an adjunct to traditional imaging modalities. Materials and Methods: The literature regarding CBCT and implant dentistry was systematically reviewed. A PubMed search that included studies published between January 1, 2000, and July 31, 2011, was conducted. Oral presentations, in conjunction with these studies, were given by Dr. Erika Benavides, Dr. Scott Ganz, Dr. James Mah, Dr. Myung-Jin Kim, and Dr. David Hatcher at a meeting of the International Congress of Oral Implantologists in Seoul, Korea, on October 6–8, 2011. Results: The studies published could be divided into four main groups: diagnostics, implant planning, surgical guidance, and postimplant evaluation. Conclusions: The literature supports the use of CBCT in dental implant treatment planning particularly in regards to linear measurements, three-dimensional evaluation of alveolar ridge topography, proximity to vital anatomical structures, and fabrication of surgical guides. Areas such as CBCT-derived bone density measurements, CBCT-aided surgical navigation, and postimplant CBCT artifacts need further research. ICOI Recommendations: All CBCT examinations, as all other radiographic examinations, must be justified on an individualized needs basis. The benefits to the patient for each CBCT scan must outweigh the potential risks. CBCT scans should not be taken without initially obtaining thorough medical and dental histories and performing a comprehensive clinical examination. CBCT should be considered as an imaging alternative in cases where the projected implant receptor or bone augmentation site(s) are suspect, and conventional radiography may not be able to assess the true regional three-dimensional anatomical presentation. The smallest possible field of view should be used, and the entire image volume should be interpreted.

Biomimetic hybrid scaffolds for engineering human tooth-ligament interfaces.

A major clinical challenge in the reconstruction of large oral and craniofacial defects is the neogenesis of osseous and ligamentous interfacial structures. Currently, oral regenerative medicine strategies are unpredictable for repair of tooth-supporting tissues destroyed as a consequence of trauma, chronic infection or surgical resection. Here, we demonstrate multi-scale computational design and fabrication of composite hybrid polymeric scaffolds for targeted cell transplantation of genetically modified human cells for the formation of human tooth dentin-ligament-bone complexes in vivo. The newly-formed tissues demonstrate the interfacial generation of parallel- and obliquely-oriented fibers that grow and traverse within the polycaprolactone (PCL)-poly(glycolic acid) (PGA) designed constructs forming tooth cementum-like tissue, ligament, and bone structures. This approach offers potential for the clinical implementation of customized periodontal scaffolds that may enable regeneration of multi-tissue interfaces required for oral, dental and craniofacial engineering applications.

Tissue engineering bone-ligament complexes using fiber-guiding scaffolds

Regeneration of bone-ligament complexes destroyed due to disease or injury is a clinical challenge due to complex topologies and tissue integration required for functional restoration. Attempts to reconstruct soft-hard tissue interfaces have met with limited clinical success. In this investigation, we manufactured biomimetic fiber-guiding scaffolds using solid free-form fabrication methods that custom fit complex anatomical defects to guide functionally-oriented ligamentous fibers in vivo. Compared to traditional, amorphous or random-porous polymeric scaffolds, the use of perpendicularly oriented micro-channels provides better guidance for cellular processes anchoring ligaments between two distinct mineralized structures. These structures withstood biomechanical loading to restore large osseous defects. Cell transplantation using hybrid scaffolding constructs with guidance channels resulted in predictable oriented fiber architecture, greater control of tissue infiltration, and better organization of ligament interface than random scaffold architectures. These findings demonstrate that fiber-guiding scaffolds drive neogenesis of triphasic bone-ligament integration for a variety of clinical scenarios.

Cell- and Gene-Based Therapeutic Strategies for Periodontal Regenerative Medicine

Inflammatory periodontal diseases are a leading cause of tooth loss and are linked to multiple systemic conditions, such as cardiovascular disease and stroke. Reconstruction of the support and function of affected tooth-supporting tissues represents an important therapeutic endpoint for periodontal regenerative medicine. An improved understanding of periodontal biology coupled with current advances in scaffolding matrices has introduced novel treatments that use cell and gene therapy to enhance periodontal tissue reconstruction and its biomechanical integration. Cell and gene delivery technologies have the potential to overcome limitations associated with existing periodontal therapies, and may provide a new direction in sustainable inflammation control and more predictable tissue regeneration of supporting alveolar bone, periodontal ligament, and cementum. This review provides clinicians with the current status of these early-stage and emerging cell- and gene-based therapeutics in periodontal regenerative medicine, and introduces their future application in clinical periodontal treatment. The paper concludes with prospects on the application of cell and gene tissue engineering technologies for reconstructive periodontology.

Immediate implant loading: current status from available literature.

The introduction of osseointegrated implants in dentistry represents a turning point in dental clinical practice. Thanks to their multiple therapeutic possibilities and the high predictability of success, implant therapy is now regarded as an extremely reliable approach to replace missing teeth. The concept of immediate implant loading has recently become popular due to less trauma, reduced overall treatment time, decreased patients anxiety and discomfort, high patient acceptance and better function and esthetics. Nonetheless, research and understanding in this area are confuse and sometimes contradictory. Hence, it is the purpose of this review to provide rational for immediate implant loading, summarize current available literature, and analyze factors that influencing this newly introduced treatment method. Results from this review indicated that immediate implant loading achieved similar high success rate as that noted in the conventional approach (delayed protocols). However, a careful case selection, proper treatment plan, meticulous surgery and proper design of prosthesis are essential for optimal outcomes when this approach is adopted.

Gene Expression Dynamics During Bone Healing and Osseointegration

BACKGROUND Understanding the molecular features of bone repair and osseointegration may aid in the development of therapeutics to improve implant outcomes. The purpose of this investigation is to determine the gene expression dynamics during alveolar bone repair and implant osseointegration. METHODS An implant osseointegration preclinical animal model was used whereby maxillary defects were created at the time of oral implant placement, while a tooth extraction socket healing model was established on the contralateral side of each animal. The surrounding tissues in the zone of the healing defects were harvested during regeneration for temporal evaluation using histology, immunohistochemistry, laser capture microdissection, and quantitative reverse transcription-polymerase chain reaction for the identification of a panel of 17 putative genes associated with wound repair. RESULTS In both models, three distinct expression patterns were displayed: 1) genes that are slowly increased during the healing process, such as bone morphogenetic protein 4, runt-related transcription factor 2, and osteocalcin; 2) genes that are upregulated at the early stage of healing and then downregulated at later stages, such as interleukin and chemokine (C-X-C motif) ligands 2 and 5; and 3) genes that are constitutively expressed over time, such as scleraxis. Although some similarities between osseointegration and tooth extraction socket were seen, distinct features developed and triggered a characteristic coordinated expression and orchestration of transcription factors, growth factors, extracellular matrix molecules, and chemokines. CONCLUSIONS Characterization of these events contributes to a better understanding of cooperative molecular dynamics in alveolar bone healing, and highlights potential pathways that could be further explored for the enhancement of osseous regenerative strategies.

A Novel Role of Periostin in Postnatal Tooth Formation and Mineralization

Periostin plays multiple functions during development. Our previous work showed a critical role of this disulfide-linked cell adhesion protein in maintenance of periodontium integrity in response to occlusal load. In this study, we attempted to address whether this mechanical response molecule played a direct role in postnatal tooth development. Our key findings are 1) periostin is expressed in preodontoblasts, and odontoblasts; and the periostin-null incisor displayed a massive increase in dentin formation after mastication; 2) periostin is also expressed in the ameloblast cells, and an enamel defect is identified in both the adult-null incisor and molar; 3) deletion of periostin leads to changes in expression profiles of many non-collagenous protein such as DSPP, DMP1, BSP, and OPN in incisor dentin; 4) the removal of a biting force leads to reduction of mineralization, which is partially prevented in periostin-null mice; and 6) both in vitro and in vivo data revealed a direct regulation of periostin by TGF-β1 in dentin formation. In conclusion, periostin plays a novel direct role in controlling postnatal tooth formation, which is required for the integrity of both enamel and dentin.