Search

The aim of our study was to review current concepts in targeted therapies for benign tumors of the jaw. Benign odontogenic and maxillofacial bone tumors often require radical surgery, with consequent morbidity that impacts patients' postsurgical quality of life. Currently, targeted therapies and novel nonsurgical therapeutics are being explored for management of non-resectable tumors, with the aim of avoiding surgery or minimizing surgical scope. However, data on clinical applications of targeted therapies for benign tumors of the jaw remain sparse. Therefore, a literature review was conducted, based on the PubMed database, which included in vivo human clinical studies describing clinical application of targeted therapy for benign tumor of the jaw. The review assessed the outcomes of BRAF and MEK inhibitors for treatment of ameloblastoma, RANKL monoclonal antibody for treatment of giant cell tumor, cherubism, aneurysmal bone cyst, and fibrous dysplasia, and tyrosine kinase inhibitor for treatment of odontogenic myxoma and cherubism. Targeted therapies decreased tumor size, slowed down tumor progression, and reduced bone pain. Surgery remains the gold standard, but targeted therapies are promising adjuvant or alternative treatment options for reducing tumor progression and morbidity of tumor surgery. [ABSTRACT FROM AUTHOR]

Purpose: Primary cilia play a significant role in mesenchymal stem cell (MSC) lineage commitment, skeletal development, and bone homeostasis. MSC responsiveness to metabolic stress is associated with radiation and drug-induced jaw osteonecrosis. Therefore, we hypothesize that orofacial MSCs (OFMSCs) osteogenic commitment in response to cellular stressors hypoxia and bisphosphonates is a survival response coupled to primary cilia biogenesis.Materials and Methods: Human OFMSCs were subjected to cellular stress using severe hypoxia, nitrogen-containing bisphosphonate (pamidronate) and low serum starvation. OFMSC primary cilia formation, as well as cell survival and proliferation, were detected using immunofluorescence, CellTitre-Glo, and WST-1 assays respectively. OFMSC differentiation was tested using Alizarin Red S staining. OFMSCs survival and osteogenic markers were assessed by western blotting relative to primary cilia number and associated acetylated tubulin levels.Results: Baseline OFMSC proliferation was stable under short-term severe hypoxia and pamidronate treatments whether combined with or without serum starvation. Hypoxia and pamidronate decreased the number of OFMSCs positive for primary cilia that was consistent with increased HIF-1α and caspase 3 but decreased cyclin D1. Combined effects of hypoxia and pamidronate on OFMSCs significantly reduced ciliation but did not completely abrogate it. Combination of serum deprivation, hypoxia, and pamidronate promoted OFMSCs osteogenic differentiation that was consistent with upregulated HIF-1α levels.Conclusions: Partial rather than complete loss of OFMSC ciliation and enhanced osteogenic commitment represent adaptive survival response of OFMSCs to severe hypoxia and pamidronate-induced metabolic stress. Hypoxia and drug-induced OFMSC stress may be significant events governing the pathogenesis and clinical outcomes of jaw osteonecrosis. [ABSTRACT FROM AUTHOR]

Objectives: Mesenchymal stem cells (MSCs) offer a promising therapy in dentistry because of their multipotent properties. Selecting donor MSCs is crucial because Beagle dogs (canines) commonly used in preclinical studies have shown variable outcomes, and it is unclear whether canine MSCs (cMSCs) are skeletal site specific. This study tested whether jaw and long bone cMSCs have disparate in vitro and in vivo multilineage differentiation capabilities.Study Design: Primary cMSCs were isolated from the mandible (M-cMSCs) and femur (F-cMSCs) of four healthy Beagle dogs. The femur served as the non-oral control. Clonogenic and proliferative abilities were assessed. In vitro osteogenic, chondrogenic, adipogenic, and neural multilineage differentiation were correlated with in vivo bone regeneration and potential for clinical applications.Results: M-cMSCs displayed two-fold increase in clonogenic and proliferative capacities relative to F-cMSCs (P = .006). M-cMSCs in vitro osteogenesis based on alkaline phosphatase (P = .04), bone sialoprotein (P = .05), and osteocalcin (P = .03), as well as adipogenesis (P = .007) and chondrogenesis (P = .009), were relatively higher and correlated with enhanced M-cMSC bone regenerative capacity. Neural expression markers, nestin and βIII-tubulin, were not significantly different.Conclusions: The enhanced differentiation and bone regenerative capacity of mandible MSCs may make them favorable donor graft materials for site-specific jaw bone regeneration. [ABSTRACT FROM AUTHOR]

The objective of this systematic review was to evaluate the risk for spontaneous occurrence of medicated-related osteonecrosis of the jaw (MRONJ) in patients with fibrous dysplasia (FD) and McCune-Albright syndrome (MAS). FD is a rare genetic disorder caused by somatic activating mutations of the GNAS locus encoding the Gsα signaling protein, resulting in reduction of GTPase activity and prolonged activation of Gsα, leading to excessive production of Cyclic adenosine monophosphate (cAMP), which disrupts the ability of bone mesenchymal stem cells to differentiate to mature osteogenic cells. With the increased use of bisphosphonates for the antiresorptive properties, the role of antiresorptives in controlling activity within FD lesions and improvement of bone quality is still inconclusive. A systematic review of the literature was performed by searching PubMed and EMBASE databases using controlled search vocabulary, namely, fibrous dysplasia, McCune-Albright syndrome, jaw, osteonecrosis, antiresorptives, antiresorptive therapy, bisphosphonate, denosumab, teriparatide, estrogen, estrogen therapy, hormone therapy, raloxifene, bazedoxifene, calcitonin, and cathepsin K inhibitor. Articles were limited to human studies, in the English language, in which patients were on antiresorptives for at least 2 years. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement guidelines were used to eliminate nonrelevant studies. The patient, intervention, comparison, outcome, and time (PICOT) question asked was, "Do antiresorptives cause spontaneous occurrence of MRONJ in patients with FD/MAS monitored for at least 2 years of therapy?" Among the 65 records screened, only 3 articles were eligible for qualitative synthesis based on PRISMA screening criteria. There were no reported cases of spontaneous MRONJ among the patients with FD/MAS across these studies. This is a significant finding among this cohort of patients. Patients with FD demonstrated low susceptibility to spontaneous occurrence of MRONJ, but more confirmatory studies are still needed. This systematic review was limited by the low number of FD/MAS eligible studies. This could be because of the rare genetic nature of FD/MAS, with low patient recruitment in clinical studies among factors. These pose significant challenges to implementing well-designed randomized placebo-controlled clinical trials that focus on antiresorptive-induced osteonecrosis of the jaw in FD/MAS. As more clinical studies become available, a future follow-up systematic review may provide additional insights into MRONJ complications in patients with FD/MAS treated with antiresorptives. [ABSTRACT FROM AUTHOR]

Objectives: Osteoradionecrosis (ORN) is common in the jaws after radiotherapy. We hypothesized that the mandible is more susceptible to ORN than the tibia, based on site disparity in hypoxic, hypocellular, and hypovascular tissue breakdown. Study Design: Twelve rats received 50 Gy irradiation to mandible or tibia; 4 of the rats further received minor surgical trauma to the irradiated sites. Structural and cellular skeletal changes were assessed with computerized tomography, histology, and immunostaining. Results: Mandible developed ORN with 70% mean bone loss 10 weeks after irradiation (P < .05), whereas tibia was structurally and radiologically intact 20 weeks after irradiation. Hypocellularity, hypoxia, and oxidative stress were higher in irradiated mandible (P < .001) than tibia (P < .01) but vascular damage was similar at both skeletal sites. Combined effects of radiation and minor trauma promoted mandibular alveolar bone loss and tibial fracture. Conclusions: ORN has a more rapid onset in mandible than in tibia in the rat. [Copyright &y& Elsevier]

Abstract: Introduction: Human orofacial bone mesenchymal stem cells (OFMSCs) from maxilla and mandible have robust osteogenic regenerative properties on the basis of our previous reports that demonstrate phenotypic and functional differences between jaw and axial bone mesenchymal stem cells in same individuals. Furthermore, a combination of OFMSCs with bioactive calcium-releasing cements can potentially improve OFMSC multilineage differentiation capacity, but biocompatibility of calcium-silicate cements with OFMSCs is still unclear. We tested the hypothesis that material extracts of calcium-releasing calcium-silicate cements support biomimetic microenvironment for survival and differentiation of human OFMSCs. Methods: Two experimental calcium-silicate cements, (1) calcium-silicate mineral powder (wTC) containing dicalcium and tricalcium-silicate, calcium sulfate, and calcium chloride and (2) wTC doped with alpha-tricalcium phosphate (wTC-αTCP), were designed and prepared. Cement setting times were assessed by Gilmore needles, ability to release calcium and hydroxyl ions was assessed by potentiometric methods, and OFMSC attachment to calcium-silicate discs was assessed. Calcium-silicate material extracts were tested for ability to support OFMSC survival and in vitro/in vivo differentiation. Results: Fewer OFMSCs attached to calcium-silicate discs relative to tissue culture plastic (P = .001). Extracts of calcium-silicate cements sustained OFMSC survival, maintained steady state levels of vascular cell adhesion molecule-1, alkaline phosphatase, and bone sialoprotein while up-regulating their respective gene transcripts. Adipogenic and in vivo bone regenerative capacities of OFMSCs were also unaffected by calcium-silicate extracts. Conclusions: Ion-releasing calcium-silicate cements support a biomimetic microenvironment conducive to survival and differentiation of OFMSCs. Combination of OFMSCs and calcium-silicate cement can potentially promote tissue regeneration in periapical bone defects. [Copyright &y& Elsevier]

Abstract: A variety of materials have been used as fillers for soft tissue augmentation. In this study, methylcellulose (MC), a water-soluble derivative of the polysaccharide cellulose, was modified with functional methacrylate groups and photocrosslinked to produce hydrogels for potential application in plastic and reconstructive surgery. Purified macromer (5% theoretical modification, 2.3% actual) was resuspended in 0.05wt.% of the photoinitiator, 2-methyl-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone, cast into custom molds, and exposed to long-wavelength UV light for 10min to form gels. Photocrosslinked MC hydrogels at varying weight/volume percentages displayed equilibrium weight swelling ratios (wet weight/dry weight) and elastic moduli of 30±3 to 17±2 and 8.48±0.25kPa to 23.21±1.55kPa, respectively, demonstrating the formation of stable gels with tunable properties. Human dermal fibroblasts grown in the presence of MC hydrogels in vitro exhibited no significant changes in cell viability after 5days of co-culture, indicating that the materials are non-cytotoxic. Higher weight percentage MC hydrogels (6%) implanted subcutaneously in CD-1 mice maintained their integrity and original dimensions after 80days in vivo, eliciting a mild inflammatory response with no observed inflammatory exudate, minimal vascular infiltration and thin translucent fibrous capsule formation of approximately 50μm in thickness. Taken together, the material and biological properties of photocrosslinked MC hydrogels suggest that they may be of use in soft tissue reconstruction. [Copyright &y& Elsevier]

Abstract: Autologous grafts from axial and appendicular bones commonly used to repair orofacial bone defects often result in unfavorable outcome. This clinical observation, along with the fact that many bone abnormalities are limited to craniofacial bones, suggests that there are significant differences in bone metabolism in orofacial, axial and appendicular bones. It is plausible that these differences are dictated by site-specificity of embryological progenitor cells and osteogenic properties of resident multipotent human bone marrow stromal cells (hBMSCs). This study investigated skeletal site-specific phenotypic and functional differences between orofacial (maxilla and mandible) and axial (iliac crest) hBMSCs in vitro and in vivo. Primary cultures of maxilla, mandible and iliac crest hBMSCs were established with and without osteogenic inducers. Site-specific characterization included colony forming efficiency, cell proliferation, life span before senescence, relative presence of surface markers, adipogenesis, osteogenesis and transplantation in immunocompromised mice to compare bone regenerative capacity. Compared with iliac crest cells, orofacial hBMSCs (OF-MSCs) proliferated more rapidly with delayed senescence, expressed higher levels of alkaline phosphatase and demonstrated more calcium accumulation in vitro. Cells isolated from the three skeletal sites were variably positive for STRO 1, a marker of hBMSCs. OF-MSCs formed more bone in vivo, while iliac crest hBMSCs formed more compacted bone that included hematopoietic tissue and were more responsive in vitro and in vivo to osteogenic and adipogenic inductions. These data demonstrate that hBMSCs from the same individuals differ in vitro and in vivo in a skeletal site-specific fashion and identified orofacial marrow stromal cells as unique cell populations. Further understanding of site-specific properties of hBMSCs and their impact on site-specific bone diseases and regeneration are needed. [Copyright &y& Elsevier]

Ameloblastoma is the most clinically significant benign odontogenic tumor of the jaws. Ameloblastomas have a locally aggressive growth pattern and a high rate of malignant transformation. The etiopathogenesis of ameloblastoma is still unknown, and there is still a paucity of information on the factors regulating the locally aggressive growth characteristics of ameloblastoma. Hypoxia and autophagy are 2 mechanistic processes associated with tumor behavior as several tumor cells induce a hypoxic microenvironment to survive. Epithelium-derived ameloblastoma cells (EPAMCs) demonstrate enhanced basal autophagy, but the roles of hypoxia and autophagy in EPAMC survival and ameloblastoma recurrence are still unknown. To understand ameloblastoma pathogenicity and behavior, the goals of this study were to assess differential expression of ameloblastoma-specific and autophagy markers in primary and recurrent ameloblastoma and to assess the roles of hypoxia and autophagy in EPAMC survival. Our hypotheses were that ameloblastoma expresses markers similar to odontogenic epithelial tissue and hypoxia induces oxidative stress and activates autophagy in EPAMCs, favoring their survival and recurrence. Primary and recurrent ameloblastoma tissues from 2 patients were immunostained with pan-cytokeratin, vimentin, and SQSTM1/p62 to assess the expression levels of ameloblastoma and autophagic markers. Additionally, EPAMCs were subjected to severe hypoxia (0.1% O 2) and then allowed to recover for 24 hours in order to define responsiveness to hypoxia based on expression levels of hypoxic (hypoxia-inducible factor [HIF]-1α), survival (phosphorylated extracellular signal-regulated kinase 1/2), and autophagic (Beclin1, phosphorylated 40S ribosomal protein S6 [pS6], SQSTM1/p62, LC3A/B) markers as detected by Western blotting. Previously characterized human odontoma-derived cells (HODCs) served as control odontogenic cells. All experiments were performed in at least triplicates. Data were analyzed as fold change relative to normoxia and expressed as mean ± standard deviation. A paired t test comparison of means was done to compare the expression of autophagy proteins when cells were under normoxia to protein expression under hypoxia and recovery conditions. The Welch 2-sample t test was used to compare fold changes from normoxia in EPAMCs and HODCs with each other. P values were adjusted for multiple comparisons using the Benjamini-Hochberg procedure. Both primary and recurrent tissue samples stained positive for pan-cytokeratin in the cytoplasm of the ameloblastoma islands. Vimentin and SQSTM1/p62 were undetectable in all samples, but the connective tissue stained positive for vimentin. Relative to normoxia, HIF-1α and SQSTM1/p62 expression was increased when the EPAMCs were reoxygenated (P =.056). pS6 levels were decreased in EPAMCs in both hypoxia (P =.005) and recovery (P =.005) compared with basal levels. Hypoxia, however, did not induce any significant changes among the remainder of the hypoxic, survival, and autophagic markers; no statistically significant difference was observed between the EPAMCs and HODCs. The results of this pilot study provide insight into the pathogenicity of ameloblastoma and the possible behavior of EPAMCs when subjected to hypoxia. Our observation of vimentin expression alongside the pan-cytokeratin pattern is consistent with an epithelial origin of both primary and recurrent ameloblastoma. In EPAMCs, canonical autophagy tended to increase with hypoxia and did not recover when cells were reoxygenated, as evident by the increased HIF-1α and SQSTM1/p62 and the reduced levels of pS6 24 hours following hypoxia. This supports EPAMCs re-establishing basal autophagy after severe hypoxia and that recurrence of ameloblastoma may be related to autophagy. [ABSTRACT FROM AUTHOR]

Article Title and Bibliographic Information: Association between oral bisphosphonate use and dental implant failure among middle-aged women. Yip JK, Borrell LN, Cho SC, Francisco H, Tarnow DP. J Clin Periodontol 2012;39:408-14. Reviewer: Sunday O. Akintoye, BDS, DDS, MS Purpose/Question: To determine whether dental implant failure is associated with history of oral bisphosphonate therapy Source of Funding: Authors'' institution provided support Type of Study/Design: Case-control study Level of Evidence: Level 2: Limited-quality, patient-oriented evidence Strength of Recommendation Grade: Not applicable [Copyright &y& Elsevier]

Article Title and Bibliographic Information: Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN. Barasch A, Cunha-Cruz J, Curro FA, Hujoel P, Sung AH, Vena D, Voinea-Griffin AE; CONDOR Collaborative Group, Beadnell S, et al. J Dent Res 2011;90(4):439-44. Reviewers: Sunday O. Akintoye, BDS, DDS, MS, Elliot V. Hersh, DMD, MS, PhD Purpose/Question: To determine risks associated with bisphosphonate therapy and identify other risk factors for osteonecrosis of the jaw (ONJ) Source of Funding: National Institute of Dental and Craniofacial Research grants U01DE016747, U01DE016755, U01DE016750, U01DE016746, U01DE016754, and U01DE016752 Type of Study/Design: Multicenter case-control study Level of Evidence: Level 2: Limited-quality, patient-oriented evidence Strength of Recommendation Grade: Not applicable [Copyright &y& Elsevier]

McCune-Albright syndrome (MAS) is a rare multisystem disorder characterized by the triad of polyostotic fibrous dysplasia (FD), endocrine disorders, and café-au-lait skin pigmentation. Ninety percent of MAS patients have FD lesions in the craniofacial area, resulting in significant orofacial deformity, dental disorders, bone pain, and compromised oral health. Maxillomandibular FD is also associated with dental developmental disorders, malocclusion, and high caries index. There are limited data on the outcomes of dental treatments in maxillomandibular FD/MAS patients, because clinicians and researchers have limited access to patients, and there are concerns that dental surgery may activate quiescent jaw FD lesions to grow aggressively. This report highlights current perspectives on dental management issues associated with maxillomandibular FD within the context of MAS. [ABSTRACT FROM AUTHOR]

Highlights • Ameloblastoma contains a highly clonogenic epithelial-derived odontogenic cell population (EP-AMCs). • EP-AMCs display strong basal levels of autophagic proteins. • EP-AMCs regenerated ameloblastoma-like tumor recapitulating similar histological features of solid multicystic ameloblastoma. • Ameloblastoma-derived cells exhibit strong basal autophagic processes that can support post-treatment recurrence. Abstract Objectives Ameloblastoma is an aggressive odontogenic jaw neoplasm. Its unlimited growth confers high potential for malignant transformation and recurrence. It is unclear why ameloblastoma is highly recurrent despite surgical resection with a wide margin of normal tissue. While canonical autophagy can be used to degrade and eliminate damaged cellular components, it is also a protective mechanism that provides energy and vital metabolites for cell survival. We used ameloblastoma-derived cells to test the hypothesis that autophagic processes play a role in survival and reactivation of ameloblastoma. Methods Primary epithelial (EP-AMCs) and mesenchymal (MS-AMCs) ameloblastoma-derived cells were established from tissue samples of solid multicystic ameloblastoma. Clonogenic capacity and basal autophagic capacity were assessed in ameloblastoma-derived cells relative to human odontoma-derived cells (HODCs) and maxilla-mesenchymal stem cells (MX-MSCs). Ability of ameloblastoma-derived cells to survive and form new ameloblastoma was assessed in mouse tumor xenografts. Results EP-AMCs were highly clonogenic (p < 0.0001) and demonstrated enhanced basal levels of autophagic proteins microtubule-associated protein 1-light chain 3 (LC3) (p < 0.01), p62 (Sequestosome 1, SQSTM1) (p < 0.01), and the LC3-adapter, melanoregulin (MREG) (p < 0.05) relative to controls. EP-AMCs xenografts regenerated solid ameloblastoma-like tumor with histological features of columnar ameloblast-like cells, loose stellate reticulum-like cells and regions of cystic degeneration characteristic of follicular variant of solid multicystic ameloblastoma. The xenografts also displayed stromal epithelial invaginations strongly reactive to LC3 and p62 suggestive of epithelial-mesenchymal transition and neoplastic odontogenic epithelium. Conclusions EP-AMCs exhibit altered autophagic processes that can support survival and recurrence of post-surgical ameloblastoma cells. [ABSTRACT FROM AUTHOR]

Cancer radiotherapy is often complicated by a spectrum of changes in the neighboring bone from mild osteopenia to osteoradionecrosis. We previously reported that parathyroid hormone (PTH, 1-34), an anabolic agent for osteoporosis, reversed bone structural deterioration caused by multiple microcomputed tomography (microCT) scans in adolescent rats. To simulate clinical radiotherapy for cancer patients and to search for remedies, we focally irradiated the tibial metaphyseal region of adult rats with a newly available small animal radiation research platform (SARRP) and treated these rats with intermittent injections of PTH1-34. Using a unique 3D image registration method that we recently developed, we traced the local changes of the same trabecular bone before and after treatments, and observed that, while radiation caused a loss of small trabecular elements leading to significant decreases in bone mass and strength, PTH1-34 preserved all trabecular elements in irradiated bone with remarkable increases in bone mass and strength. Histomorphometry demonstrated that SARRP radiation severely reduced osteoblast number and activity, which were impressively reversed by PTH treatment. In contrast, suppressing bone resorption by alendronate failed to rescue radiation-induced bone loss and to block the rescue effect of PTH1-34. Furthermore, histological analyses revealed that PTH1-34 protected osteoblasts and osteocytes from radiation-induced apoptosis and attenuated radiation-induced bone marrow adiposity. Taken together, our data strongly support a robust radioprotective effect of PTH on trabecular bone integrity through preserving bone formation and shed light on further investigations of an anabolic therapy for radiation-induced bone damage. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Orofacial bone is commonly affected by osteoradionecrosis (ORN) during head and neck cancer radiotherapy possibly due to interactions of several factors including radiation damage to resident bone marrow stromal cells (BMSCs). Irradiation causes DNA damage, triggers p53-dependent signalling resulting in either cell-cycle arrest or apoptosis. In same individuals, disproportionately higher rapid growth of orofacial BMSCs relative to those of axial/appendicular bones suggests their response to radiation is skeletally site-specific. We hypothesised that survival and osteogenic recovery capacity of irradiated human BMSCs is site-dependent based on anatomic skeletal site of origin. Methods: Early passage BMSCs from maxilla, mandible and iliac crest of four normal volunteers were exposed to 2.5 to 10Gy gamma radiation to evaluate clonogenic survival, effects on cell cycle, DNA damage, p53-related response and in vivo osteogenic regenerative capacity. Results: Orofacial bone marrow stromal cells (OF-MSCs) survived higher radiation doses and recovered quicker than iliac crest (IC-MSCs) based on clonogenic survival, proliferation and accumulation in G0G1 phase. Post-irradiation p53 level was relatively unchanged but expression of p21, a downstream effector was moderately increased in OF-MSCs. Re-establishment of in vivo bone regeneration was delayed more in irradiated IC-MSCs relative to OF-MSCs. Conclusions: Effect of irradiation on human BMSCs was skeletal site-specific with OF-MSCs displaying higher radio-resistance and quicker recovery than IC-MSCs. [Copyright &y& Elsevier]